Hemostatic devices and methods of use

ABSTRACT

An anchorage device is provided that is configured to surround an implantable medical device. The anchorage device includes a substrate and a hemostatic agent. The substrate includes a first piece and a second piece that is joined with the first piece. The first piece includes the hemostatic agent and the second piece includes an active pharmaceutical ingredient. Kits, systems and methods are disclosed.

TECHNICAL FIELD

The present disclosure generally relates to anchorage devices andmethods configured for anchoring an implantable medical device within abody, wherein the anchorage device comprises at least one hemostaticagent that is configured to elute over time.

BACKGROUND

Some known anchorage devices may be used to secure an implantablemedical device within a body of a patient. The anchorage device andimplantable medical device can be inserted into a desired locationwithin the body of the patient. The anchorage device can be used to helpanchor or support the implantable medical device to surrounding tissue.Some known anchorage devices are used to provide temporary support totissue during a healing process. For example, some known anchoragedevices can secure one portion of tissue to another portion of tissue.

Pocket hematoma is a frequent complication following deviceimplantation. For example, it is estimated that hematomas account forabout 15 to 20% early intervention after pacemaker or ImplantableCardioverter Defibrillator (ICD) implantations. The development of aclinically significant pocket hematoma increases the risk of aninfection by a factor or 7.7×. While increased use of anticoagulanttherapy has been assigned as a possible cause, it's use cannot betotally discounted due to the danger of thromboembolic events, includingcerebral stroke. Hematomas may increase pain, require re-interventionfor draining, and delay healing. There is an unmet clinical need toaddress postoperative bleeding in the pectoral pocket related to CardiacImplantable Electronic Device (CIEO) procedures in order to reduce theincidence of hematoma. It would be desirable to stop or reduce the flowof blood at a surgical site and/or speed up the blood clotting processwhile anchoring the implantable medical device to tissue. Thisdisclosure describes an improvement over these prior art technologies.

SUMMARY

New anchorage devices and methods are provided to help anchor or supportan implantable medical device to surrounding tissue. In one embodiment,an anchorage device is provided that includes a substrate and ahemostatic agent.

In some embodiments, the substrate is configured to control betweenabout 20 cc and about 50 cc of blood. In some embodiments, the substrateis configured to control less than 20 cc of blood. In some embodiments,the substrate is configured to control more than 50 cc of blood. In someembodiments, the substrate is configured to be effective to controlbleeding for about 5 days to about 7 days. In some embodiments, thesubstrate is configured to be effective to control bleeding less than 5days. In some embodiments, the substrate is configured to be effectiveto control bleeding for more than 7 days. In some embodiments, thesubstrate includes a polymer and is configured to retain anti-microbialproperties of the polymer.

In some embodiments, the substrate comprises a first piece and a secondpiece that is joined with the first piece, the first piece comprisingthe hemostatic agent and the second piece comprising an activepharmaceutical ingredient. In some embodiments, the first and secondpieces form a hemostatic envelope, pouch, or pocket in which, one sideof the hemostatic envelope, pouch, or pocket includes an opening toallow a device, such as, for example, the implantable medical device tobe inserted through the opening and into a cavity of the hemostaticenvelope, pouch, or pocket.

In some embodiments, the anchorage device substrate is a hemostaticsheet, which can be folded or otherwise manipulated to enclose a device,such as, for example, an implantable medical device within the sheet orsubstrate. That is, the sheet includes a first side and an oppositesecond side. In some embodiments, the hemostatic agent is applied to thefirst side and/or the second side. In some embodiments, the hemostaticagent is applied to the first side and an active pharmaceuticalingredient is applied to the second side.

In some embodiments, the anchorage device includes a polymer that isapplied to the substrate. In some embodiments, the polymer covers all ora portion of the substrate. In some embodiments, the polymer includesthe hemostatic agent such that the hemostatic agent elutes over time inan area surrounding or adjacent to the anchorage device. In someembodiments, the polymer also includes an active pharmaceuticalingredient such that the active pharmaceutical agent elutes over time inthe area surrounding or adjacent to the anchorage device. In someembodiments, the anchorage device includes a first polymer that includesa hemostatic agent and a second polymer that includes an activepharmaceutical ingredient.

In some embodiments, the substrate includes the hemostatic agent. Thatis, the substrate is made from the hemostatic agent. In someembodiments, the substrate that is made from the hemostatic agent has anactive pharmaceutical ingredient applied to the substrate. In someembodiments, a polymer including the active pharmaceutical ingredient isapplied to the substrate such that the active pharmaceutical agentelutes over time in the area surrounding or adjacent to the anchoragedevice.

In some embodiments, the substrate is a mesh. In some embodiments, thesubstrate is a thin walled structure, such as, for example, a wafer,sheet or tissue.

Additional features and advantages of various embodiments will be setforth in part in the description that follows, and in part will beapparent from the description, or may be learned by practice of variousembodiments. The objectives and other advantages of various embodimentswill be realized and attained by means of the elements and combinationsparticularly pointed out in the description and appended claims.

BRIEF DESCRIPTION OF THE DRAWINGS

The present disclosure will become more readily apparent from thespecific description accompanied by the following drawings, in which:

FIG. 1 is a side view of one embodiment of an anchorage device inaccordance with the principles of the present disclosure;

FIG. 2 is a perspective view of one embodiment of the anchorage deviceshown in FIG. 1 in accordance with the principles of the presentdisclosure;

FIG. 3 is a perspective view of one embodiment of the anchorage deviceshown in FIG. 1 in accordance with the principles of the presentdisclosure;

FIG. 4 is a perspective view of one embodiment of the anchorage deviceshown in FIG. 1 in accordance with the principles of the presentdisclosure;

FIG. 5 is a perspective view of one embodiment of the anchorage deviceshown in FIG. 1 in accordance with the principles of the presentdisclosure;

FIG. 6 is a perspective view of one embodiment of the anchorage deviceshown in FIG. 1 in accordance with the principles of the presentdisclosure;

FIG. 7 is a perspective view of one embodiment of the anchorage deviceshown in FIG. 6;

FIG. 8 is a perspective view of one embodiment of the anchorage deviceshown in FIG. 1 in accordance with the principles of the presentdisclosure;

FIG. 9 is a perspective view of one embodiment of the anchorage deviceshown in FIG. 8;

FIG. 10 is a perspective view of one embodiment of the anchorage deviceshown in FIG. 8;

FIG. 11 is a perspective view of one embodiment of an anchorage devicein accordance with the principles of the present disclosure;

FIG. 12 is a depiction of the mechanism of action for a hemostatic agentin accordance with the principles of the present disclosure;

FIG. 13 is a table showing results for Example 2;

FIG. 14 is a perspective view of an anchorage device discussed inExample 9 in accordance with the principles of the present disclosure;

FIG. 15 is a perspective view of an anchorage device discussed inExample 9 in accordance with the principles of the present disclosure;

FIG. 16 is a perspective view of an anchorage device discussed inExample 9 in accordance with the principles of the present disclosure;

FIG. 17 is a perspective view of an anchorage device discussed inExample 9 in accordance with the principles of the present disclosure;

FIG. 18 is a table showing results for Example 13;

FIG. 19 is a graph showing drug content by weight of anchorages devicediscussed in Example 13;

FIG. 20A is a graph showing elution profiles of Samples 1 and 2discussed in Example 13;

FIG. 20B is a graph showing elution profiles of Samples 3 and 4discussed in Example 13;

FIG. 20C is a graph showing elution profiles of Samples 5 and 6discussed in Example 13;

FIG. 20D is a graph showing elution profiles of Samples 9 and 10discussed in Example 13;

FIG. 20E is a graph showing elution profiles of Samples 11 and 12discussed in Example 13;

FIG. 20F is a table showing the expected drug content of Samples 1-6 and9-12 in Example 13;

FIG. 20G is a table showing elution results for Samples 1-6 in Example13;

FIG. 20H is a table showing elution results for Samples 9-12 in Example13;

FIG. 201 is a table showing elution results for Samples 9-12 in Example13;

FIG. 20J is a table showing elution results for Samples 9-12 in Example13;

FIG. 20K is a table showing elution results for Samples 9-12 in Example13;

FIG. 20L includes a graph showing drug release profiles for samplesdiscussed in Example 13;

FIG. 20M includes a graph showing drug release profiles for samplesdiscussed in Example 13;

FIG. 20N includes a graph showing drug release profiles for samplesdiscussed in Example 13;

FIG. 200 includes a graph showing drug release profiles for samplesdiscussed in Example 13;

FIG. 20P includes a graph showing drug release profiles for samplesdiscussed in Example 13;

FIG. 20Q includes a graph showing drug release profiles for samplesdiscussed in Example 13;

FIG. 20R includes a graph showing drug release profiles for samplesdiscussed in Example 13;

FIG. 20S includes a graph showing drug release profiles for samplesdiscussed in Example 13;

FIG. 20T includes a graph showing drug release profiles for samplesdiscussed in Example 13;

FIG. 21 includes graphs showing results discussed in Example 14;

FIG. 22 includes graphs showing results discussed in Example 15;

FIG. 23 is a graph showing results discussed in Example 16;

FIG. 24 is a graph showing results discussed in Example 17;

FIG. 25 is a graph showing results discussed in Example 18;

FIG. 26 includes slides showing results discussed in Example 19;

FIG. 27 includes images of samples discussed in Example 21; and

FIG. 28 includes a graph showing results discussed in Example 17.

DETAILED DESCRIPTION

For the purposes of this specification and appended claims, unlessotherwise indicated, all numbers expressing quantities of ingredients,percentages or proportions of materials, and other numerical values usedin the specification and claims, are to be understood as being modifiedin all instances by the term “about.” Accordingly, unless indicated tothe contrary, the numerical parameters set forth in the followingspecification and attached claims are approximations that may varydepending upon the desired properties sought to be obtained by thepresent invention. At the very least, and not as an attempt to limit theapplication of the doctrine of equivalents to the scope of the claims,each numerical parameter should at least be construed in light of thenumber of reported significant digits and by applying ordinary roundingtechniques.

Notwithstanding the numerical ranges and parameters set forth herein,the broad scope of the invention are approximations, the numericalvalues set forth in the specific examples are reported as precisely aspossible. Any numerical value, however, inherently contains certainerrors necessarily resulting from the standard deviation found in theirrespective testing measurements. Moreover, all ranges disclosed hereinare to be understood to encompass any and all subranges subsumedtherein. For example, a range of “1 to 10” includes any and allsubranges between (and including) the minimum value of 1 and the maximumvalue of 10, that is, any and all subranges having a minimum value ofequal to or greater than 1 and a maximum value of equal to or less than10, e.g., 5.5 to 10.

Reference will now be made in detail to certain embodiments of theinvention, examples of which are illustrated in the accompanyingdrawings. While the invention will be described in conjunction with theillustrated embodiments, it will be understood that they are notintended to limit the invention to those embodiments. On the contrary,the invention is intended to cover all alternatives, modifications, andequivalents that may be included within the invention as defined by theappended claims.

This disclosure is directed to anchorage devices, such as, for example,an anchorage device 20. In some embodiments, the components of anchoragedevice 20 can be fabricated from biologically acceptable materialssuitable for medical applications, including metals, synthetic polymers,allografts, xenografts, isografts, ceramics and bone material and/ortheir composites, depending on the particular application and/orpreference of a medical practitioner. For example, the components ofanchorage device 20, individually or collectively, can be fabricatedfrom materials such as stainless steel alloys, commercially puretitanium, titanium alloys, Grade 5 titanium, super-elastic titaniumalloys, cobalt-chrome alloys, stainless steel alloys, superelasticmetallic alloys (e.g., Nitinol, super elasto-plastic metals, such as GUMMETAL® manufactured by Toyota Material Incorporated of Japan), ceramicsand composites thereof such as calcium phosphate (e.g., SKELITE™manufactured by Biologix Inc.), thermoplastics such aspolyaryletherketone (PAEK) including polyetheretherketone (PEEK),polyetherketoneketone (PEKK) and polyetherketone (PEK), carbon-PEEKcomposites, PEEK-BaSO₄ polymeric rubbers, polyethylene terephthalate(PET), fabric, silicone, polyurethane, silicone-polyurethane copolymers,polymeric rubbers, polyolefin rubbers, hydrogels, semi-rigid and rigidmaterials, elastomers, rubbers, thermoplastic elastomers, thermosetelastomers, elastomeric composites, rigid polymers includingpolyphenylene, polyamide, polyimide, polyetherimide, polyethylene,tyrosine polyarylate, epoxy, bone material including autograft,allograft, xenograft or transgenic cortical and/or corticocancellousbone, and tissue growth or differentiation factors, partially resorbablematerials, such as, for example, composites of metals and calcium-basedceramics, composites of PEEK and calcium based ceramics, composites ofPEEK with resorbable polymers, totally resorbable materials, such as,for example, calcium based ceramics such as calcium phosphate,tri-calcium phosphate (TCP), hydroxyapatite (HA)-TCP, calcium sulfate,or other resorbable polymers such as polylactide, polyglycolide,polytyrosine carbonate, polycaroplactone and their combinations.

Various components of anchorage device 20 may have material composites,including the above materials, to achieve various desiredcharacteristics such as strength, rigidity, elasticity, compliance,biomechanical performance, durability and radiolucency or imagingpreference. The components of anchorage device 20, individually orcollectively, may also be fabricated from a heterogeneous material suchas a combination of two or more of the above-described materials. Thecomponents of anchorage device 20 may be monolithically formed,integrally connected or include fastening elements and/or instruments,as described herein.

Substrate

Anchorage device 20 includes a substrate, such as, for example,substrate 22. Substrate 22 is configured to be coupled to and/or appliedto a device, such as, for example, an implantable medical device or anon-implantable medical device, as discussed herein. In someembodiments, substrate 22 is configured to surround and/or enclose atleast a portion of the implantable medical device, as discussed herein.Substrate 22 is configured to be secured to tissue to support theimplantable medical device at a treatment site. Implantable medicaldevices include, for example, neurostimulators, vascular devices such asgrafts (e.g., abdominal aortic aneurysm grafts, etc.), stents, catheters(including arterial, intravenous, blood pressure, stent graft, etc.),valves (e.g., polymeric or carbon mechanical valves,), embolicprotection filters (including distal protection devices), vena cavafilters, aneurysm exclusion devices, artificial hearts, cardiac jackets,and heart assist devices (including left ventricle assist devices),implantable defibrillators, subcutaneous implantable defibrillators,implantable monitors, for example, implantable cardiac monitors,electrostimulation devices and leads (including pacemakers, leadadapters and lead connectors), implanted medical device power supplies,peripheral cardiovascular devices, atrial septal defect closures, leftatrial appendage filters, valve annuloplasty devices, mitral valverepair devices, vascular intervention devices, ventricular assist pumps,and vascular access devices (including parenteral feeding catheters,vascular access ports, central venous access catheters).

Implantable medical devices may also include, for example, surgicaldevices such as sutures of all types, anastomosis devices (includinganastomotic closures), suture anchors, hemostatic barriers, screws,plates, clips, vascular implants, tissue scaffolds, cerebro-spinal fluidshunts, shunts for hydrocephalus, drainage tubes, catheters includingthoracic cavity suction drainage catheters, abscess drainage catheters,biliary drainage products, and implantable pumps. Implantable medicaldevices may also include, for example, orthopedic devices such as jointimplants, acetabular cups, patellar buttons, bone repair/augmentationdevices, spinal devices (e.g., vertebral disks and the like), bone pins,cartilage repair devices, and artificial tendons. Implantable medicaldevices may also include, for example, dental devices such as dentalimplants and dental fracture repair devices. Implantable medical devicesmay also include, for example, drug delivery devices such as drugdelivery pumps, implanted drug infusion tubes, drug infusion catheters,and intravitreal drug delivery devices. Implantable medical devices mayalso include, for example, ophthalmic devices such as scleral bucklesand sponges, glaucoma drain shunts and intraocular lenses.

Implantable medical devices may also include, for example, urologicaldevices such as penile devices (e.g., impotence implants), sphincter,urethral, prostate, and bladder devices (e.g., incontinence devices,benign prostate hyperplasia management devices, prostate cancerimplants, etc.), urinary catheters including indwelling (“Foley”) andnon-indwelling urinary catheters, and renal devices. Implantable medicaldevices may also include, for example, synthetic prostheses such asbreast prostheses and artificial organs (e.g., pancreas, liver, lungs,heart, etc.). Implantable medical devices may also include, for example,respiratory devices including lung catheters. Implantable medicaldevices may also include, for example, neurological devices such asneurostimulators, neurological catheters, neurovascular ballooncatheters, neuro-aneurysm treatment coils, and neuropatches, splints,ear wicks, ear drainage tubes, tympanostomy vent tubes, otologicalstrips, laryngectomy tubes, esophageal tubes, esophageal stents,laryngeal stents, salivary bypass tubes, and tracheostomy tubes.Implantable medical devices may also include, for example, oncologicalimplants. Implantable medical devices may also include, for example,pain management implants.

In some embodiments, substrate 22 is configured to be coupled to and/orapplied to or to surround and/or enclose at least a portion of anon-implantable medical device, as discussed herein. Non-implantabledevices can include dialysis devices and associated tubing, catheters,membranes, and grafts; autotransfusion devices; vascular and surgicaldevices including atherectomy catheters, angiographic catheters,intraaortic balloon pumps, intracardiac suction devices, blood pumps,blood oxygenator devices (including tubing and membranes), bloodfilters, blood temperature monitors, hemoperfusion units, plasmapheresisunits, transition sheaths, dialators, intrauterine pressure devices,clot extraction catheters, percutaneous transluminal angioplastycatheters, electrophysiology catheters, breathing circuit connectors,stylets (vascular and non-vascular), coronary guide wires, peripheralguide wires; dialators (e.g., urinary, etc.); surgical instruments (e.g.scalpels and the like); endoscopic devices (such as endoscopic surgicaltissue extractors, esophageal stethoscopes); and general medical andmedically related devices including blood storage bags, umbilical tape,membranes, gloves, surgical drapes, wound dressings, wound managementdevices, needles, percutaneous closure devices, transducer protectors,pessary, uterine bleeding patches, PAP brushes, clamps (includingbulldog clamps), cannulae, cell culture devices, materials for in vitrodiagnostics, chromatographic support materials, infection controldevices, colostomy bag attachment devices, birth control devices;disposable temperature probes; and pledgets.

Substrate 22 can have a variety of different configurations, shapes andsizes. For example, substrate 22 can be provided with a size and shapeor other configuration that can provide the functionality of supportingand immobilizing the implantable medical device at a treatment sitewithin a patient's body, while also improving the removability ofanchorage device 20 after the treatment has been completed. In someembodiments, the implantable medical device can be disposed within apocket defined by substrate 22 and anchorage device 20 can be implantedand secured to tissue at a desired treatment site within a body of apatient. As discussed herein, during implantation, scar tissue can format the treatment site and/or tissue can become ingrown within substrate22. After the treatment is completed, the implantable medical device canremain in the patient as discussed below or can be removed from thepatient leaving anchorage device 20 implanted. To remove anchoragedevice 20, tissue that is ingrown within substrate 22 can be cut orotherwise detached from substrate 22. In some embodiments, a portion ofanchorage device 20 may not be removable from the tissue and will remainimplanted within the patient.

Substrate 22 may be formed with one or more biocompatible materials,which may be synthetic or naturally occurring. In some embodiments, theone or more biocompatible materials include, for example, polypropylene,polyester, polytetrafluoroethylene, polyamides, silicones, polysulfones,metals, alloys, titanium, stainless steel, shape memory metals (e.g.Nitinol), and/or combinations thereof.

In some embodiments, substrate 22 is configured to be implantedtemporarily within a body of a patient and/or is configured to beremoved (e.g., explanted) from the patient's body after a period oftime. In such embodiments, substrate 22 may include a non-biodegradablematerial and/or a non-bioresorbable material. For example, substrate 22may be made entirely from a non-biodegradable material and/or anon-bioresorbable material such that substrate 22 is made only from thenon-biodegradable material and/or non-bioresorbable material. In someembodiments, substrate 22 may include one or more non-biodegradableand/or a non-bioresorbable material and one or more biodegradable and/orresorbable material. In some embodiments, one side of substrate 22 mayinclude one or more non-biodegradable and/or a non-bioresorbablematerial and another side of substrate 22 can include one or morebiodegradable and/or resorbable material.

As used herein, the term “biodegradable” refers to, for example, amaterial that can be at least partially broken down or degraded by abodily fluid and discarded as waste from the body and/or a material thatcan be broken down or degraded by a living organism. Thus,“non-biodegradable” can refer to a material that cannot be broken downor degraded by a bodily fluid and/or cannot be broken down or degradedby a living organism. As used herein the term “resorbable” refers to,for example, a material that can be at least partially broken down ordegraded by a bodily fluid and assimilated within the body. Thus, a“non-resorbable” material as used herein can refer to, for example, amaterial that cannot be broken down or degraded by bodily fluid andassimilated within the body.

In some embodiments, the biocompatible biodegradable and/orbioresorbable material or materials may include polymeric and/ornon-polymeric materials, such as, for example, one or more poly(alpha-hydroxy acids), poly (lactide-co-glycolide) (PLGA), polylactide(PLA), poly(L-lactide), polyglycolide (PG), polyethylene glycol (PEG)conjugates of poly (alpha-hydroxy acids), polyorthoesters (POE),polyaspirins, polyphosphazenes, collagen, hydrolyzed collagen, gelatin,hydrolyzed gelatin, fractions of hydrolyzed gelatin, elastin, starch,pre-gelatinized starch, hyaluronic acid, chitosan, alginate, albumin,fibrin, vitamin E analogs, such as alpha tocopheryl acetate, d-alphatocopheryl succinate, D,L-lactide, or L-lactide, -caprolactone,dextrans, vinylpyrrolidone, polyvinyl alcohol (PVA), PVA-g-PLGA,PEGT-PBT copolymer (polyactive), methacrylates, poly(N-isopropylacrylamide), PEO-PPO-PEO (pluronics), PEO-PPO-PAAcopolymers, PLGA-PEO-PLGA, PEG-PLG, PLA-PLGA, poloxamer 407,PEG-PLGA-PEG triblock copolymers, POE, SAIB (sucrose acetateisobutyrate), polydioxanone, methylmethacrylate (MMA), MMA andN-vinylpyyrolidone, polyamide, oxycellulose, copolymer of glycolic acidand trimethylene carbonate, polyesteramides, tyrosine polyarylates,polyetheretherketone, polymethylmethacrylate, silicone, hyaluronic acid,chitosan, or combinations thereof. In one embodiment, substrate 22comprises Glycoprene, which is sold by Poly-Med, Inc. As used herein,the term “glycoprene” or “Glycoprene” refers to Glycoprene® orGlycoprene II®. Glycoprene® can refer to different variations of thematerial sold under the trade name Glycoprene®, such as, for example,Glycoprene® 6829, Glycoprene® 8609 and Glycoprene® 7027.

In some embodiments, the biocompatible non-biodegradable and/ornon-bioresorbable material or materials may include polymeric and/ornon-polymeric materials, such as, for example, polyurethane, polyester,polytetrafluoroethylene (PTFE),polyethylacrylate/polymethylmethacrylate, polylactide,polylactide-co-glycolide, polyamides, polydioxanone, polyvinyl chloride,polymeric or silicone rubber, collagen, thermoplastics, or combinationsthereof.

In some embodiments, substrate 22 is configured to be permanentlyimplanted within a body of a patient. In such embodiments, substrate 22may include a biodegradable material and/or a bioresorbable material.For example, substrate 22 may be made entirely from a biodegradablematerial and/or a bioresorbable material such that substrate 22 is madeonly from the biodegradable material and/or bioresorbable material.

In some embodiments, substrate 22 is provided in the form of a mesh, asshown in FIGS. 1-10. In some embodiments, the mesh is web or fabric witha construction of knitted, braided, woven or non-woven filaments orfibers F that are interlocked in such a way to create a fabric or afabric-like material that includes a matrix of filaments that definemultiple pores P. That is, the space between adjacent filaments orfibers F define pores P of the mesh. Pores P may be beneficial to allowtissue in-growth, for example. In some embodiments, apertures may beformed in the mesh by cutting the filaments or fibers F to decrease theareal density (e.g., surface density) or mass of the mesh and/or furtherfacilitate tissue in-growth. In some embodiments, the apertures thatextend through the filaments or fibers F are larger than pores P definedby the filaments or fibers F.

In some embodiments, substrate 22 is provided in the form of a thinwalled structure, such as, for example, a wafer, sheet or tissue. Insome embodiments, the thin walled structure does not include any poresor apertures, in contrast to the mesh discussed herein. In someembodiments, the thin walled structure includes pores or apertures thatare smaller than the pores or apertures of the mesh discussed herein. Insome embodiments, the thin walled structure has a thickness that is lessthan a thickness of the mesh discussed herein. In some embodiments, thethickness of the thin walled structure is between about 0.001 inches andabout 0.1 inches.

In some embodiments, substrate 22 is a planar sheet, as shown in FIG. 2.In some embodiments, the planar sheet is in the form of a mesh. In someembodiments, the planar sheet is in the form of a thin walled structure.The planar sheet has a first side and an opposite second side, similarto a sheet of paper. The planar sheet can be manipulated about all oronly a portion of an implantable medical device, such as, for example,one of the implantable medical devices discussed herein. In someembodiments, the planar sheet is moldable or bendable about theimplantable medical device. That is, the planar sheet can be bentwithout breaking the planar sheet. In some embodiments, the planar sheetcan be manipulated to form a tube, for example. In some embodiments, theplanar sheet has a rigid configuration. That is, the planar sheet cannotbe bent without breaking the planar sheet. In some embodiments, theplanar sheet can be secured to tissue to support the implantable medicaldevice at the treatment site. The planar sheet can be variously shaped,such as, for example, circular, oval, oblong, triangular, rectangular,square, polygonal, irregular, uniform, non-uniform, variable and/ortapered.

In some embodiments, substrate 22 is a scaffold, a sponge, woven,non-woven, knitted or non-knitted. In some embodiments, substrate 22 canbe formed by extrusion.

In some embodiments, substrate 22 is a pocket or envelope in which animplantable medical device can be at least partially disposed. That is,substrate 22 is a pouch, bag, covering, shell, or receptacle. Forexample, substrate 22 can include a first piece 22 a and a second piece22 b that is joined with first piece 22 a. First and second pieces 22 a,22 b are joined to form the pocket or envelope. In some embodiments,first and second pieces 22 a, 22 b are joined along three sides of thepocket or envelope to form a cavity C, as shown in FIG. 6, for example.First and second pieces 22 a, 22 b are not joined at a fourth side ofthe pocket or envelope to define an opening O such that an implantablemedical device can be inserted through opening O and into cavity C toenclose, encase or surround all or a portion of the implantable medicaldevice within cavity C. In some embodiments, first and second pieces 22a, 22 b are joined with one another along three sides of the pocket orenvelope by heat, ultrasonically, bonding, knitting, or adhesive. Insome embodiment, the pocket or envelope is monolithically formed bymolding the pocket or envelope or producing the pocket or envelope by 3Dprinting, for example.

In some embodiments, anchorage device 20 includes one or a plurality ofarms, such as, for example, extensions 22 c that extend outwardly fromthe pocket formed by first and second pieces 22 a, 22 b, as shown inFIG. 11. In some embodiments, extensions 22 c are spaced apart from oneanother and/or are positioned radially about the pocket. In someembodiments, at least one of extensions 22 c includes one or a pluralityof openings 23 that extends through a thickness of extension 22 c.Openings 23 are spaced apart along a length of extension 23. In someembodiments, openings 23 each have the same width or diameter. In someembodiments, openings 23 each have an oval or oblong shape. Extensions22 c are configured to be coupled to tissue when anchorage device 20 isinserted into an area, such as, for example, a body cavity to secure animplantable medical device within the pocket to the body. In someembodiments, at least one of extensions 22 c is made from abiodegradable and/or resorbable material. In some embodiments, at leastone of extensions 22 c is made from a biodegradable and/or resorbablematerial that degrades and/or resorbs at a faster rate than the pocketsuch that the pocket with the implantable medical device within thepocket remains after extensions 22 c degrade and/or resorb. In someembodiments, at least one of extensions 23 is made from a single layerof material to allow extensions to degrade and/or resorb at a fasterrate than the pocket, which is formed from two layers of material (e.g.,first and second pieces 22 a, 22 b). In some embodiments, extensions 22c and first and second pieces 22 a, 22 b are made from the samematerial. In some embodiments, extensions 22 c and first and secondpieces 22 a, 22 b are made different materials. In some embodiments, atleast one of extensions 22 c is made from a first material and at leastone of extensions 22 c is made from a second material that is differentthan the first material. The first and second materials may include anyof the materials discussed herein. In some embodiments, at least one ofextensions 22 c is made from a hemostatic material. In some embodiments,at least one of extensions 22 c has a hemostatic agents, such as, forexample, one or more of the hemostatic agents discussed herein, appliedto extensions 22 c. The hemostatic agent may be applied to extensions 22c in the same manner the hemostatic agents discussed herein are appliedto substrate 22. In some embodiments, extensions 22 c each have the sameamount of the hemostatic agent. In some embodiments, at least one ofextensions 22 c has a first amount of the hemostatic agent and at leastone of extensions 22 c has a second amount of the hemostatic agent thatis different than the first amount. In some embodiments, at least one ofextensions 22 c includes a first hemostatic agent and at least one ofextensions 22 c includes a second hemostatic agent that is differentthan the first hemostatic agent. In some embodiments, at least one ofextensions 22 c includes an active pharmaceutical ingredient, such as,for example, one or more of the active pharmaceutical ingredientsdiscussed herein, in addition to in in place of the hemostatic agent. Insome embodiments, at least one of extensions 22 c may be cut orotherwise severed from the pocket before or after anchorage device isimplanted within a patient. In some embodiments, at least one ofextensions 22 c is scored to facilitate the removal of extensions 22 cfrom the pocket. This allows a medical practitioner to customizeanchorage device 20 such that anchorage device only includes the amountof extensions 22 c required to secure anchorage device 20 within apatient. That is, any extraneous extensions 22 c can be removed prior toor after implantation of anchorage device 20.

In some embodiments, first and second pieces 22 a, 22 b are portions ofa single sheet that is bent to produce a fold at one end of the pocketor envelope. First and second pieces 22 a, 22 b are joined along sidesof the pocket or envelope that extend transverse to the fold such thatthe fold and the sides of the pocket or envelope do not have anyopenings. First and second pieces 22 a, 22 b are not joined at an end ofthe pocket or envelope opposite the fold to define an opening at the endsuch that a medical device can be inserted through the opening and intoa cavity defined by inner surfaces of first and second pieces 22 a, 22b.

In some embodiments, first and second pieces 22 a, 22 b each include amesh discussed herein. In some embodiments, first piece 22 a includes amesh including pores having a first size and second piece 22 b includesa mesh including pores having a second size, wherein the first size isdifferent than the first size. In some embodiments, the first size isgreater than the second size. In some embodiments, the first size isless than the second size. In some embodiments, first and second pieces22 a, 22 b each include a thin walled structure discussed herein. Insome embodiments one of first and second pieces 22 a, 22 b includes amesh discussed herein and the other one of first and second pieces 22 a,22 b includes a thin walled structure discussed herein that does nothave any pores or apertures.

In some embodiments, first and second pieces 22 a, 22 b are formed fromthe same material. In some embodiments one of first and second pieces 22a, 22 b is formed from a first material, such as, for example, one ofthe materials discussed herein, and the other one of first and secondpieces 22 a, 22 b is made from a second material, such as, for example,one of the materials discussed herein, wherein the second material isdifferent than the first material. For example, first piece 22 a may beformed from a biodegradable and/or bioresorbable material and secondpiece 22 b may be formed from a non-biodegradable and/ornon-bioresorbable material, or vice versa. In some embodiments, firstand second pieces 22 a, 22 b are each formed from a biodegradable and/orbioresorbable material, wherein the biodegradable and/or bioresorbablematerials degrade and/or resorb at the same rate. In some embodiments,first and second pieces 22 a, 22 b are formed from differentbiodegradable and/or bioresorbable materials, wherein one of thebiodegradable and/or bioresorbable materials degrades and/or resorbsmore quickly than the other biodegradable and/or bioresorbable material.

In some embodiments, first and second pieces 22 a, 22 b each include asingle layer of material, such as, for example, one of the materialsdiscussed herein. In some embodiments, at least one of first and secondpieces 22 a, 22 b includes multiple layers. In some embodiments, themultiple layers include more than one layer of the mesh discussedherein. In some embodiments, the multiple layers include more than onelayer of the thin walled structure discussed herein. In someembodiments, the multiple layers include one or more layer of the meshdiscussed herein and one or more layer of the thin walled structurediscussed herein. In some embodiments, the multiple layers include oneor more layer of the mesh discussed herein and one or more layer of thethin walled structure discussed herein, wherein one of the layers ofmesh is positioned between two layers of the thin walled structure. Insome embodiments, the multiple layers include one or more layer of themesh discussed herein and one or more layer of the thin walled structurediscussed herein, wherein one of the layers of thin walled structure ispositioned between two layers of the mesh.

Hemostatic Agent(s)

Anchorage device 20 includes an agent, such as, for example, ahemostatic agent 24. Hemostatic agent 24 can include one more hemostaticagent, such as, for example, epinephrine, tranexamic acid, chitosan andoxidized regenerated cellulose. In some embodiments, hemostatic agent 24can include one or more of Spongostan®, Surgifoam®, Avitene, thrombinand Ostene® in addition to or in place of the hemostatic agentsdiscussed above. In some embodiments, hemostatic agent 24 can includeone or more of protamine, norepinephrine, desmopressin, lysine analogs,collagen, gelatin, polysaccharide spheres, mineral zeolite, bovinethrombin, pooled human thrombin, recombinant thrombin, gelatin andthrombin, collagen and thrombin, cyanacrylate, fibrin glue, polyethyleneglycol, and glutaraldehyde in addition to or in place of the hemostaticagents discussed above. In some embodiments, the lysine analog istranexamic acid and has the formula:

In some embodiments, the anchorage devices disclosed herein utilize oneor more pharmacologic hemostatic agent since pharmacologic hemostaticagents have been found to be desirable over mechanical hemostats for avariety of reasons. Ethnographic research has showed that physiciansdesire a hemostat that can provide an extended elution profile to reducebleeding events for up to 7 days post operatively. Furthermore, there isa possible effect on handling and/or allergic reactions if mechanicalhemostats, such as, for example, oxidized reduced cellulose or chitosanwere used.

In some embodiments, tranexamic acid is preferred for use as hemostaticagent 24. Tranexamic acid is a synthetic analog of the amino acid lysinewith a molecular weight of 157 g/mol. Tranexamic acid is anantifibrinolytic agent that acts by binding to plasminogen and blockingthe interaction of plasminogen with fibrin, therefore preventing thedissolution of a fibrin clot. In the presence of a wound, fibrinolysisoccurs naturally when a lysine residue such as tissue plasminogenactivator (tPA), binds to plasmin causing the clot to lyse (or break).Tranexamic acid blocks tPA and keeps the clot from breaking, thuspreventing unwanted bleeding. FIG. 12 depicts this process.

Prior to a damaged endothelium, tPA is inhibited in the blood byplasminogen activator inhibitor/type 1 (PAI-1). Once damage occurs, thetPA is released slowly into the blood, activating fibrinolysis.Excessive fibrinolysis results in a condition called hvperfibrinolysis,which requires intervention such as fibrinogen, plasma, transfusion orantifibrinolytic therapy, such as tranexamic acid.

Tranexamic acid has been used for over 40 years to reduce bleedingcomplications. Tranexamic acid is most commonly given systemically atdoses of 10 mg/kg followed by infusion of 10 mg/kg/h. Since 2007,tranexamic acid has received widespread approval and clinical use as ahemostatic agent. Knowing that surgical trauma causes fibrinolysis inthe area of the surgical wound itself, topical antifibrinolytic therapyis becoming more common to obtain and maintain hemostasis. Clinicaltrials with topical tranexamic acid use exist for cardiac surgery, CIEDprocedures, orthopedic surgery, spinal surgery, dental extraction andepistaxis, and breast mammoplasty.

To evaluate the efficacy of tranexamic acid, a non-GLP acute porcinestudy was conducted. Doses of 1 mg to 200 mg of tranexamic acid wereused in an in vitro whole blood coagulation test, a hepatic biopsy test,and a subcutaneous ICD surgical procedure.

The in vitro whole blood coagulation test showed no activity fortranexamic acid up to 10 mg/ml. The maximum tranexamic acidconcentration, 200 mg/5 ml, was a slightly higher dose than that usedclinically in a CIED pocket if 50 cc is the assumed blood volume ofinterest. Coagulation time was doubled with this higher dose.

The hepatic biopsy test had a volume of 0.016 ml when the biopsy holewas filled with blood. The minimum tranexamic acid dose evaluated was2.5 mg, which is equivalent to 156 mg/ml. This concentration preventsblood from clotting quickly and these biopsies continued to bleed pastthe endpoint of 10 minutes. This phenomenon is likely due to themultiple bonding sites available to tranexamic acid in whole blood, andthe fact that a biopsy does not induce fibrinolysis.

The subcutaneous surgical site test was conducted with an elevated ACTusing heparin to induce hematoma. Surgical trauma similar to that of aCIEO implant was incurred in each pocket, but some subcutaneous pocketsincurred more trauma than others due to anatomical location. The primaryoutput monitored was accumulated blood as measured by pre-weighed gauze3-hours post-operatively. With only one animal, and two pockets pertreatment, the sample size was too low to show any significance betweenICD only, ICD+polymer, and ICD+polymer+tranexamic acid.

The non-GLP acute porcine study showed that in the dose range evaluated,tranexamic acid has a two-fold increase on clotting time and no effecton reducing bleeding on the hepatic biopsies. In the heparinized ICDpocket procedure, 3.5-22.8 grams of blood accumulated in a 3-hour periodof time regardless of treatment. It appears that subcutaneous pockets inan anticoagulated porcine model would be a translatable model forevaluating efficacy of tranexamic acid because it has a relevant volumeof accumulated blood and surgical trauma similar to that of a CIEDprocedure.

Based upon the non-GLP acute porcine study, tranexamic acidconcentrations of 3.00 mg/L to 30 mg/L are effective in preventingfibrinolysis. As such, in some embodiments, hemostatic agent 24 istranexamic acid and is provided in concentrations of about 3.00 mg/L toabout 30 mg/L. However, it has been found that one tenth of the dosesused in the non-GLP acute porcine study can be effective in reversingfibrinolysis. As such, in some embodiments, hemostatic agent 24 istranexamic acid and is provided in concentrations of about 0.30 mg/L toabout 3.0 mg/L for intravenous applications. In some embodiments,tranexamic acid is provided in concentrations of about 3.78 mg/L toabout 30 mg/L for topical applications as well. However, in someembodiments, however, higher doses of tranexamic acid are used fortopical applications to account for tranexamic acid being widelydistributed throughout the extracellular and intracellular compartmentswhen given preoperatively. Indeed, it has been found that tranexamicacid reaches plasma concentrations in 5-15 minutes. As such, in someembodiments, tranexamic acid is provided in doses of about 1.5 mg toabout 150 mg.

In some embodiments, hemostatic agent 24 includes a mixture orcombination of the hemostatic agents discussed herein. In someembodiments, hemostatic agent 24 is applied directly to substrate 22, asshown in FIG. 2. That is, hemostatic agent 24 is not applied tosubstrate 22 in a polymer, such as, for example, a polymer that includeshemostatic agent 24. In some embodiments, hemostatic agent 24 may beapplied to substrate 22 by spraying hemostatic agent 24 onto substrate22, coating all or a portion of substrate 22 with hemostatic agent 24,coating all or a portion of substrate 22 with a material, such as, forexample, applying a polymer to substrate 22 that includes hemostaticagent 24, washing substrate 22 with hemostatic agent 24, or printinghemostatic agent 24 on substrate 22 with a printer, such as, for examplea 3D printer.

In some embodiments, hemostatic agent 24 is a material that formssubstrate 22, as shown in FIG. 3. That is, substrate 22 is made fromhemostatic agent 24. In some embodiments, substrate 22 is made only fromhemostatic agent 24.

In embodiments discussed herein wherein anchorage device 20 is a planarsheet, the planar sheet has opposite top and bottom surfaces andhemostatic agent 24 can be applied to at least one of the top and bottomsurfaces. That is, hemostatic agent 24 may be applied to both the topand bottom surfaces, or only one of the top and bottom surfaces. In someembodiments, a first hemostatic agent 24 is applied to the top surfaceand a second hemostatic agent 24 is applied to the bottom surface,wherein the first hemostatic agent 24 is different than the secondhemostatic agent 24. In some embodiments, a first hemostatic agent 24 isapplied to the top surface and a second hemostatic agent 24 is appliedto the bottom surface, wherein the first hemostatic agent 24 includes adifferent amount of hemostatic agent 24 than the second hemostatic agent24.

In embodiments discussed herein wherein anchorage device 20 is a pocketor envelope, hemostatic agent 24 can be applied to at least one of firstpiece 22 a and second piece 22 b. In some embodiments, only one of firstand second pieces 22 a, 22 b includes hemostatic agent 24. In someembodiments, hemostatic agent 24 is applied only to opposite outersurfaces of first and second pieces 22 a, 22 b. That is, the innersurfaces of first and second pieces 22 a, 22 b that face one another anddefine cavity C do not have hemostatic agent 24 applied thereto. In someembodiments, hemostatic agent 24 is applied only to the inner surfacesof first and second pieces 22 a, 22 b that define cavity C. That is, theopposite outer surfaces of first and second pieces 22 a, 22 b that faceaway from one another do not have hemostatic agent 24 applied thereto.In some embodiments, hemostatic agent 24 is applied only to the innersurface of one of first and second pieces 22 a, 22 b and to the outersurface of the other one of first and second pieces 22 a, 22 b.

In embodiments discussed herein wherein anchorage device 20 is a pocketor envelope, a first hemostatic agent 24 can be applied to first piece22 a and a second hemostatic agent 24 can be applied to second piece 22b, wherein the second hemostatic agent 24 is different than the firsthemostatic agent 24. In some embodiments, a first hemostatic agent 24 isapplied to the outer surfaces of first and second pieces 22 a, 22 b anda second hemostatic agent 24 is applied to the inner surfaces of firstand second pieces 22 a, 22 b, wherein the second hemostatic agent 24 isdifferent than the first hemostatic agent 24.

Hemostatic agent 24 is configured to elute from anchorage device 20 intoan area surrounding or adjacent to anchorage 20 to reduce or preventbleeding within a patient, such as, for example, bleeding caused by asurgical procedure. The amount of hemostatic agent 24 that is applied tosubstrate 22 can be varied to elute a selected amount of hemostaticagent 24 and/or to elute hemostatic agent 24 at a selected rate and/orto elute hemostatic agent over a selected number of hours or days. Insome embodiments, hemostatic agent 24 is eluted into surrounding bodilytissue, bodily fluid, or systemic fluid, to reduce or prevent bleeding.In some embodiments, hemostatic agent 24 may be eluted for up to 30days. In some embodiments, between about 40% and about 100% ofhemostatic agent 24 is eluted over a period of at least about 30 hours.In some embodiments, 60% and about 100% of hemostatic agent 24 is elutedover a period of at least about 30 hours. In some embodiments, betweenabout 65% and about 100% of hemostatic agent 24 is eluted over a periodof at least about 36 hours. In some embodiments, 80% and about 100% ofhemostatic agent 24 is eluted over a period of at least about 36 hours.In some embodiments, between about 60% and about 100% of hemostaticagent 24 is eluted over a period of at least about 48 hours. In someembodiments, 80% and about 100% of hemostatic agent 24 is eluted over aperiod of at least about 48 hours. In some embodiments, between about60% and about 100% of hemostatic agent 24 is eluted over a period of atleast about 60 hours. In some embodiments, 80% and about 100% ofhemostatic agent 24 is eluted over a period of at least about 60 hours.

In some embodiments, anchorage device 20 may include a polymer that isapplied to and/or coats at least a portion of substrate 22, wherein thepolymer includes hemostatic agent 24. That is, hemostatic agent 24 isapplied to substrate 22 via the polymer. In some embodiments, thepolymer includes a combination, blend or mixture of polymers. In someembodiments, the polymer is configured to degrade within a patient andreleases hemostatic agent 24 as the polymer degrades. In someembodiments, the degradation rate of the polymer is known or can bepredicted to allow a medical practitioner to select a polymer or aquantity of polymer that is applied to substrate 22 to produce anchoragedevice 20 that is customized to elute a selected quantity of hemostaticagent 24 at a selected rate over a selected period of time. For example,the polymer may be selected to elute a selected quantity of hemostaticagent 24 per hour or day for a selected number of days or hours.

In some embodiments, the polymer is selected from the group consistingof polylactic acid, polyglycolic acid, poly(L-lactide),poly(D,L-lactide)polyglycolic acid[polyglycolide],poly(L-lactide-co-D,L-lactide), poly(L-lactide-co-glycolide),poly(D,L-lactide-co-glycolide), poly(glycolide-co-trimethylenecarbonate), poly(D,L-lactide-co-caprolactone),poly(glycolide-co-caprolactone), polyethylene oxide, polydioxanone,polypropylene fumarate, poly(ethyl glutamate-co-glutamic acid),poly(tert-butyloxy-carbonylmethyl glutamate), polycaprolactone,polycaprolactone co-butylacrylate, polyhydroxybutyrate, copolymers ofpolyhydroxybutyrate, poly(phosphazene), poly(phosphate ester),poly(amino acid), polydepsipeptides, maleic anhydride copolymers,polyiminocarbonates, poly[(97.5% dimethyl-trimethylenecarbonate)-co-(2.5% trimethylene carbonate)], poly(orthoesters),tyrosine-derived polyarylates, tyrosine-derived polycarbonates,tyrosine-derived polyiminocarbonates, tyrosine-derived polyphosphonates,polyethylene oxide, polyethylene glycol, polyalkylene oxides,hydroxypropylmethylcellulose, polysaccharides such as hyaluronic acid,chitosan and regenerate cellulose. In some embodiments, the polymer mayinclude combinations, blends or mixtures of the polymers discussedherein.

In some embodiments, the polymer is a polyarylate. In some embodiments,the polymer is a tyrosine-derived polyarylate. In some embodiments, thetyrosine-derived polyarylate is p(DTE co X % DT succinate), where X isabout 10% to about 30%. In some embodiments, the tyrosine-derivedpolyarylate is p(DTE co X % DT succinate), where X ranges from about26.5% to about 28.5%. In some embodiments, the tyrosine-derivedpolyarylate is p(DTE co X % DT succinate), where X is about 27.5%. Insome embodiments, the polymer is P22-27.5 DT.

As used herein, DTE is the diphenol monomer desaminotyrosyl-tyrosineethyl ester; DTBn is the diphenol monomer desaminotyrosyl-tyrosinebenzyl ester; DT is the corresponding free acid form, namelydesaminotyrosyl-tyrosine. BTE is the diphenol monomer 4-hydroxy benzoicacid-tyrosyl ethyl ester; BT is the corresponding free acid form, namely4-hydroxy benzoic acid-tyrosine.

P22-XX is a polyarylate copolymer produced by condensation of DTE andDTBn with succinic acid followed by removal of benzyl group. P22-10,P22-15, P22-20, P22-XX, etc., represents copolymers different percentageof DT (i.e., 10, 15, 20 and % DT, etc.) In some embodiments, the polymeris produced by condensation of DTBn with succinic acid followed byremoval of benzyl group. This polymer is represented as P02-100.

In some embodiments, the polymer includes one or more polyarylates thatare copolymers of desaminotyrosyl-tyrosine (DT) and andesaminotyrosyl-tyrosyl ester (DT ester), wherein the copolymercomprises from about 0.001% DT to about 80% DT and the ester moiety canbe a branched or unbranched alkyl, alkylaryl, or alkylene ether grouphaving up to 18 carbon atoms, any group of which can, optionally have apolyalkylene oxide therein. Similarly, another group of polyarylates arethe same as the foregoing but the desaminotyrosyl moiety is replaced bya 4-hydroxybenzoyl moiety. In some embodiments, the DT or BT contentsinclude those copolymers with from about 1% to about 30%, from about 5%to about 30% from about 10 to about 30% DT or BT. In some embodiments,the diacids (used informing the polyarylates) include succinate,glutarate and glycolic acid.

In some embodiments, the polymer includes one or more biodegradable,resorbable polyarylates and polycarbonates. These polymers, include, butare not limited to, BTE glutarate, DTM glutarate, DT propylamideglutarate, DT glycineamide glutarate, BTE succinate, BTM succinate, BTEsuccinate PEG, BTM succinate PEG, DTM succinate PEG, DTM succinate, DTN-hydroxysuccinimide succinate, DT glucosamine succinate, DT glucosamineglutarate, DT PEG ester succinate, DT PEG amide succinate, DT PEG esterglutarate, DT PEG ester succinate, DTMB P(Desaminotyrsoyl tyrosinemethylparaben ester-glutarate), and DTPP P(Desaminotyrsoyl tyrosinepropylparaben ester-glutarate).

In some embodiments, the polymer is one more polymers from the DTE-DTsuccinate family of polymers, e.g., the P22-xx family of polymers havingfrom 0-50%, 5-50%, 5-40%, 1-30% or 10-30% DT, including but not limitedto, about 1, 2, 5, 10, 15, 20, 25, 27.5, 30, 35, 40%, 45% and 50% DT. Insome embodiments, the polymer is P22-27.5 DT.

In some embodiments, the polymer has diphenol monomer units that arecopolymerized with an appropriate chemical moiety to form a polyarylate,a polycarbonate, a polyiminocarbonate, a polyphosphonate or any otherpolymer.

In some embodiments, the polymer is tyrosine-based polyarylate. In someembodiments, the polymer includes blends and copolymers withpolyalkylene oxides, including polyethylene glycol (PEG).

In some embodiments, the polymer can have from 0.1-99.9% PEG diacid topromote the degradation process. In some embodiments, the polymerincludes blends of polyarylates or other biodegradable polymers withpolyarylates.

The polymer is configured to release hemostatic agent 24 over time, asdiscussed herein. In some embodiments, the polymer is configured torelease hemostatic agent 24 over a time period ranging from about 1 hourto about 168 hours. In some embodiments, the polymer is configured torelease hemostatic agent 24 over a time period ranging from 1 hour to 72hours. In some embodiments, the polymer is configured to releasehemostatic agent 24 over a time period ranging from 1 hour to 24 hours.

In some embodiments, the polymer is configured to release hemostaticagent 24 over time in an area surrounding or adjacent to anchoragedevice 20 (such as, for example, within the device “pocket” or within 3inches in all dimensions). In some embodiments, the polymer isconfigured to release hemostatic agent 24 for up to 30 hours. In someembodiments, the polymer is configured to release between about 40% andabout 100% of hemostatic agent 24 over a period of at least about 30hours. In some embodiments, the polymer is configured to release 60% andabout 100% of hemostatic agent 24 over a period of at least about 30hours. In some embodiments, the polymer is configured to release betweenabout 65% and about 100% of hemostatic agent 24 over a period of atleast about 36 hours. In some embodiments, the polymer is configured torelease 80% and about 100% of hemostatic agent 24 over a period of atleast about 36 hours. In some embodiments, the polymer is configured torelease between about 60% and about 100% of hemostatic agent 24 over aperiod of at least about 48 hours. In some embodiments, the polymer isconfigured to release 80% and about 100% of hemostatic agent 24 over aperiod of at least about 48 hours. In some embodiments, the polymer isconfigured to release between about 60% and about 100% of hemostaticagent 24 over a period of at least about 60 hours. In some embodiments,the polymer is configured to release 80% and about 100% of hemostaticagent 24 over a period of at least about 60 hours. In some embodiments,the polymer is configured to release 80% and about 100% of hemostaticagent 24 within 48 hours. In some embodiments, the polymer is configuredto release 80% and about 100% of hemostatic agent 24 within 24 hours.

In some embodiments, the polymer is configured to release no more than60% of hemostatic agent 24 within 24 hours. In some embodiments, thepolymer is configured to release no more than 90% of hemostatic agent 24after 60 hours. In some embodiments, the polymer is configured torelease no more than 50% of hemostatic agent 24 within 12 hours. In someembodiments, the polymer is configured to release between about 40% andabout 90% between 12 and 24 hours. In some embodiments, the polymer isconfigured to release between about 60% and about 100% between 24 and 36hours. In some embodiments, the polymer is configured to release betweenabout 65% and about 100% between 36 and 48 hours. In some embodiments,the polymer is configured to release between about 70% and about 100%between 48 and 60 hours.

Substrate 22 may be coated with single or multiple coating layers of thepolymer, depending on, for example, the amount of hemostatic agent 24 tobe delivered and desired release rate. Each layer of the polymer maycontain the same or different amounts of hemostatic agent 24. Forexample, a first layer of the polymer may contain hemostatic agent 24,while the second layer of the polymer contains either no hemostaticagent 24 or a lower concentration of hemostatic agent 24. As anotherexample, a first layer of the polymer may comprise hemostatic agent 24in a first polymer, while the second layer of the polymer compriseshemostatic agent 24 in a second polymer that is different than the firstpolymer.

In embodiments discussed herein wherein anchorage device 20 is a planarsheet, a first polymer can be applied to the top surface of the sheetand a second polymer can be applied to the bottom surface of the sheet.In some embodiments, the first and second polymers are differentpolymers. In some embodiments, the first and second polymers releasehemostatic agent 24 at different rates and/or over different lengths oftime. In some embodiments, the first and second polymers are differentpolymers, and the first polymer includes a first amount of hemostaticagent 24 and the second polymer includes a second amount of hemostaticagent 24, the first amount being different than the second amount. Insome embodiments, the first and second polymers are the same polymer,wherein the first polymer includes a first amount of hemostatic agent 24and the second polymer includes a second amount of hemostatic agent 24,the first amount being different than the second amount.

In embodiments discussed herein wherein anchorage device 20 is a pocketor envelope, a first polymer can be applied to first piece 22 a and asecond polymer can be applied to second piece 22 b. In some embodiments,the first and second polymers are different polymers. In someembodiments, the first and second polymers release hemostatic agent 24at different rates and/or over different lengths of time. In someembodiments, the first and second polymers are different polymers, andthe first polymer includes a first amount of hemostatic agent 24 and thesecond polymer includes a second amount of hemostatic agent 24, thefirst amount being different than the second amount. In someembodiments, the first and second polymers are the same polymer, whereinthe first polymer includes a first amount of hemostatic agent 24 and thesecond polymer includes a second amount of hemostatic agent 24, thefirst amount being different than the second amount. In someembodiments, a first polymer is applied to the outer surfaces of firstand second pieces 22 a, 22 b and a second polymer is applied to theinner surfaces of first and second pieces 22 a, 22 b, wherein the firstpolymer includes a first amount of hemostatic agent 24 and the secondpolymer includes a second amount of hemostatic agent 24, the firstamount being different than the second amount. In some embodiments, thefirst amount is more than the second amount. In some embodiments, thefirst amount is less than the second amount.

Active Pharmaceutical Ingredient(s)

In some embodiments, anchorage device 20 includes an ingredient, suchas, for example, an active pharmaceutical ingredient 26. Activepharmaceutical ingredient 26 is applied to substrate 22 to such thatanchorage device 20 delivers hemostatic agent 24 in combination withactive pharmaceutical ingredient 26. In some embodiments, activepharmaceutical ingredient 26 is applied directly to substrate 22. Thatis, active pharmaceutical ingredient 26 is not applied to substrate 22in a polymer, such as, for example, a polymer that includes activepharmaceutical ingredient 26. In some embodiments, active pharmaceuticalingredient 26 is applied to substrate 22 via a polymer, such as, forexample, one of the polymers discussed herein, wherein the polymerincludes active pharmaceutical ingredient 26 and releases activepharmaceutical agent 26 as the polymer degrades. In some embodiments,active pharmaceutical ingredient 26 is applied to substrate 22 via apolymer that includes hemostatic agent 24. In some embodiments, activepharmaceutical ingredient 26 is applied to substrate 22 via a polymerthat does not include hemostatic agent 24, such as, for example, apolymer that is free of hemostatic agent 24.

Active pharmaceutical ingredient 26 can include one or a combination ofactive pharmaceutical ingredients, such as, for example, anesthetics,antibiotics, anti-inflammatory agents, procoagulant agents,fibrosis-inhibiting agents, antiseptics, anti-scarring agents,leukotriene inhibitors/antagonists, cell growth inhibitors and mixturesthereof. In some embodiments, active pharmaceutical ingredient 26 is anantibiotic. In some embodiments, the antibiotic is selected from thegroup consisting of rifampin and minocycline and mixtures thereof.

Examples of non-steroidal anti-inflammatories include, but are notlimited to, naproxen, ketoprofen, ibuprofen as well as diclofenac;celecoxib; sulindac; diflunisal; piroxicam; indomethacin; etodolac;meloxicam; r-flurbiprofen; mefenamic; nabumetone; tolmetin, and sodiumsalts of each of the foregoing; ketorolac bromethamine; ketorolacbromethamine tromethamine; choline magnesium trisalicylate; rofecoxib;valdecoxib; lumiracoxib; etoricoxib; aspirin; salicylic acid and itssodium salt; salicylate esters of alpha, beta, gamma-tocopherols andtocotrienols (and all their d, 1, and racemic isomers); and the methyl,ethyl, propyl, isopropyl, n-butyl, sec-butyl, t-butyl, esters ofacetylsalicylic acid.

Examples of anesthetics include, but are not limited to, licodaine,bupivacaine, and mepivacaine. Further examples of analgesics,anesthetics and narcotics include, but are not limited to acetaminophen,clonidine, benzodiazepine, the benzodiazepine antagonist flumazenil,lidocaine, tramadol, carbamazepine, meperidine, zaleplon, trimipraminemaleate, buprenorphine, nalbuphine, pentazocain, fentanyl, propoxyphene,hydromorphone, methadone, morphine, levorphanol, and hydrocodone. Localanesthetics have weak antibacterial properties and can play a dual rolein the prevention of acute pain and infection.

Examples of antibacterial agents or antimicrobials include, but are notlimited to, triclosan, chlorohexidine and other cationic biguanides,rifampin, minocycline (or other tetracycline derivatives), vancomycin,gentamycin; gendine; genlenol; genfoctol; clofoctol; cephalosporins andthe like. Further antibacterial agents or antimicrobials includeaztreonam; cefotetan and its disodium salt; loracarbef; cefoxitin andits sodium salt; cefazolin and its sodium salt; cefaclor; ceftibuten andits sodium salt; ceftizoxime; ceftizoxime sodium salt; cefoperazone andits sodium salt; cefuroxime and its sodium salt; cefuroxime axetil;cefprozil; ceftazidime; cefotaxime and its sodium salt; cefadroxil;ceftazidime and its sodium salt; cephalexin; hexachlorophene;cefamandole nafate; cefepime and its hydrochloride, sulfate, andphosphate salt; cefdinir and its sodium salt; ceftriaxone and its sodiumsalt; cefixime and its sodium salt; cetylpyridinium chloride; ofoxacin;linexolid; temafloxacin; fleroxacin; enoxacin; gemifloxacin;lomefloxacin; astreonam; tosufloxacin; clinafloxacin; cefpodoximeproxetil; chloroxylenol; methylene chloride, iodine and iodophores(povidone-iodine); nitrofurazone; meropenem and its sodium salt;imipenem and its sodium salt; cilastatin and its sodium salt;azithromycin; clarithromycin; dirithromycin; erythromycin andhydrochloride, sulfate, or phosphate salts ethylsuccinate, and stearateforms thereof, clindamycin; clindamycin hydrochloride, sulfate, orphosphate salt; lincomycin and hydrochloride, sulfate, or phosphate saltthereof, tobramycin and its hydrochloride, sulfate, or phosphate salt;streptomycin and its hydrochloride, sulfate, or phosphate salt;vancomycin and its hydrochloride, sulfate, or phosphate salt; neomycinand its hydrochloride, sulfate, or phosphate salt; acetyl sulfisoxazole;colistimethate and its sodium salt; quinupristin; dalfopristin;amoxicillin; ampicillin and its sodium salt; clavulanic acid and itssodium or potassium salt; penicillin G; penicillin G benzathine, orprocaine salt; penicillin G sodium or potassium salt; carbenicillin andits disodium or indanyl disodium salt; piperacillin and its sodium salt;a-terpineol; thymol; taurinamides; nitrofurantoin; silver-sulfadiazine;hexetidine; methenamine; aldehydes; azylic acid; silver; benzylperoxide; alcohols; carboxylic acids; salts; nafcillin; ticarcillin andits disodium salt; sulbactam and its sodium salt; methylisothiazolone,moxifloxacin; amifloxacin; pefloxacin; nystatin; carbepenems; lipoicacids and its derivatives; beta-lactams antibiotics; monobactams;aminoglycosides; microlides; lincosamides; glycopeptides; tetracyclines;chloramphenicol; quinolones; fucidines; sulfonamides; macrolides;ciprofloxacin; ofloxacin; levofloxacins; teicoplanin; mupirocin;norfloxacin; sparfloxacin; ketolides; polyenes; azoles; penicillins;echinocandines; nalidixic acid; rifamycins; oxalines; streptogramins;lipopeptides; gatifloxacin; trovafloxacin mesylate; alatrofloxacinmesylate; trimethoprims; sulfamethoxazole; demeclocycline and itshydrochloride, sulfate, or phosphate salt; doxycycline and itshydrochloride, sulfate, or phosphate salt; minocycline and itshydrochloride, sulfate, or phosphate salt; tetracycline and itshydrochloride, sulfate, or phosphate salt; oxytetracycline and itshydrochloride, sulfate, or phosphate salt; chlortetracycline and itshydrochloride, sulfate, or phosphate salt; metronidazole; dapsone;atovaquone; rifabutin; linezolide; polymyxin B and its hydrochloride,sulfate, or phosphate salt; sulfacetamide and its sodium salt; andclarithromycin (and combinations thereof). In some embodiments, thepolymer may contain rifampin and another antimicrobial agent, such as,for example, an antimicrobial agent that is a tetracycline derivative.In some embodiments, the polymer contains a cephalosporin and anotherantimicrobial agent. In some embodiments, the polymer containscombinations including rifampin and minocycline, rifampin andgentamycin, and rifampin and minocycline.

When a mixture of two antibiotics is used, they generally present in aratio ranging from about 10:1 to about 1:10. In some embodiments, amixture of rifampin and minocycline are used. In those embodiments, aratio of rifampin to minocycline ranges from about 5:2 to about 2:5. Inother embodiments, the ratio of rifampin to minocycline is about 1:1.

Examples of antifungals include amphotericin B; pyrimethamine;flucytosine; caspofungin acetate; fluconazole; griseofulvin; terbinafineand its hydrochloride, sulfate, or phosphate salt; amorolfine; triazoles(Voriconazole); flutrimazole; cilofungin; LY303366 (echinocandines);pneumocandin; imidazoles; omoconazole; terconazole; fluconazole;amphotericin B, nystatin, natamycin, liposomal amptericin B, liposomalnystatins; griseofulvin; BF-796; MTCH 24; BTG-137586; RMP-7/AmphotericinB; pradimicins; benanomicin; ambisome; ABLC; ABCD; Nikkomycin Z;flucytosine; SCH 56592; ER30346; UK 9746; UK 9751; T 8581; LY121019;ketoconazole; micronazole; clotrimazole; econazole; ciclopirox;naftifine; and itraconazole.

In some embodiments, active pharmaceutical ingredient 26 includeskeflex, acyclovir, cephradine, malphalen, procaine, ephedrine,adriamycin, daunomycin, plumbagin, atropine, quinine, digoxin,quinidine, biologically active peptides, cephradine, cephalothin,cis-hydroxy-L-proline, melphalan, penicillin V, aspirin, nicotinic acid,chemodeoxycholic acid, chlorambucil, paclitaxel, sirolimus,cyclosporins, 5-fluorouracil and the like.

In some embodiments, active pharmaceutical ingredient 26 includes one ormore ingredients that act as angiogenensis inhibitors or inhibit cellgrowth such as epidermal growth factor, PDGF, VEGF, FGF (fibroblastgrowth factor) and the like. These ingredients include anti-growthfactor antibodies (neutrophilin-1), growth factor receptor-specificinhibitors such as endostatin and thalidomide. Examples of usefulproteins include cell growth inhibitors such as epidermal growth factor.

Examples of anti-inflammatory compounds include, but are not limited to,anecortive acetate; tetrahydrocortisol,4,9(11)-pregnadien-17α,21-diol-3,20-dione and its -21-acetate salt;111-epicortisol; 17α-hydroxyprogesterone; tetrahydrocortexolone;cortisona; cortisone acetate; hydrocortisone; hydrocortisone acetate;fludrocortisone; fludrocortisone acetate; fludrocortisone phosphate;prednisone; prednisolone; prednisolone sodium phosphate;methylprednisolone; methylprednisolone acetate; methylprednisolone,sodium succinate; triamcinolone; triamcinolone-16,21-diacetate;triamcinolone acetonide and its -21-acetate, -21-disodium phosphate, and-21-hemisuccinate forms; triamcinolone benetonide; triamcinolonehexacetonide; fluocinolone and fluocinolone acetate; dexamethasone andits -21-acetate, -21-(3,3-dimethylbutyrate), -21-phosphate disodiumsalt, -21-diethylaminoacetate, -21-isonicotinate, -21-dipropionate, and-21-palmitate forms; betamethasone and its -21-acetate, -21-adamantoate,-17-benzoate, -17,21-dipropionate, -17-valerate, and -21-phosphatedisodium salts; beclomethasone; beclomethasone dipropionate;diflorasone; diflorasone diacetate; mometasone furoate; andacetazolamide.

Examples of leukotriene inhibitors/antagonists include, but are notlimited to, leukotriene receptor antagonists such as acitazanolast,iralukast, montelukast, pranlukast, verlukast, zafirlukast, andzileuton.

In some embodiments, active pharmaceutical ingredient 26 includes sodium2-mercaptoethane sulfonate (“MESNA”). MESNA has been shown to diminishmyofibroblast formation in animal studies of capsular contracture withbreast implants [Ajmal et al. (2003) Plast. Reconstr. Surg.112:1455-1461] and may thus act as an anti-fibrosis agent.

Procoagulants include, but are not limited to, zeolites, thrombin, andcoagulation factor concentrates.

In some embodiments, the amount of active pharmaceutical ingredient 26that is applied to substrate 22 ranges between about 0.3 to about 150micrograms/cm². In other embodiments, the amount of activepharmaceutical ingredient 26 that is applied to substrate 22 rangesbetween about 0.6 to about 1.4 micrograms/cm². In yet other embodiments,the amount of active pharmaceutical ingredient 26 that is applied tosubstrate 22 ranges between about 0.85 to about 1.20 micrograms/cm². Inyet further embodiments, the amount of active pharmaceutical ingredient26 that is applied to substrate 22 ranges between about 0.90 to about1.10 micrograms/cm². In yet further embodiments, the amount of activepharmaceutical ingredient 26 that is applied to substrate 22 rangesbetween about 50 to about 150 micrograms/cm². In yet furtherembodiments, 62 micrograms/cm² of active pharmaceutical ingredient 26 isapplied to substrate 22. In yet further embodiments, 140 micrograms/cm²of active pharmaceutical ingredient 26 is applied to substrate 22.

In other embodiments, active pharmaceutical ingredient 26 includesrifampin and minocycline and the amount of each of rifampin andminocycline that is applied to substrate 22 ranges between about 0.6 toabout 1.4 micrograms/cm². In yet other embodiments, the amount of eachof rifampin and minocycline that is applied to substrate 22 rangesbetween about 0.85 to about 1.20 micrograms/cm². In yet furtherembodiments, the amount of each of rifampin and minocycline that isapplied to substrate 22 ranges between about 0.90 to about 1.10micrograms/cm².

Active pharmaceutical agent 26 may include any of the activepharmaceutical ingredients discussed herein. Active pharmaceutical agent26 may be incorporated into anchorage device 20 by applying activepharmaceutical ingredient 26 directly to substrate 22 or by applyingactive pharmaceutical ingredient 26 to substrate 22 via a polymer, suchas, for example, one or more of the polymers discussed herein. Doses ofthe active pharmaceutical ingredients discussed herein are known and theamounts of any single active pharmaceutical ingredient to include inanchorage device 20 can readily be surmised. Any pharmaceuticallyacceptable form of the active pharmaceutical ingredients discussedherein can be employed in anchorage device 20, e.g., the free base or apharmaceutically acceptable salt or ester thereof. Pharmaceuticallyacceptable salts, for instance, include sulfate, lactate, acetate,stearate, hydrochloride, tartrate, maleate, citrate, phosphate and thelike.

In some embodiments, active pharmaceutical ingredient 26 is applieddirectly to substrate 22, as discussed herein. In some embodiments,active pharmaceutical ingredient 26 may be applied to substrate 22 byspraying active pharmaceutical ingredient 26 onto substrate 22, coatingall or a portion of substrate 22 with active pharmaceutical ingredient26, coating all or a portion of substrate 22 with a material, such as,for example, one or more polymer that includes active pharmaceuticalingredient 26, washing substrate 22 with active pharmaceuticalingredient 26, or printing active pharmaceutical ingredient 26 onsubstrate 22 with a printer, such as, for example a 3D printer. In someembodiments, active pharmaceutical ingredient 26 is a material thatforms substrate 22. That is, substrate 22 is made from activepharmaceutical ingredient 26 and hemostatic agent 24 is applied tosubstrate 22.

In some embodiments, active pharmaceutical ingredient 26 is positionedbetween hemostatic agent 24 and substrate 22, as shown in FIG. 4. Assuch, hemostatic agent 24 forms a top layer of anchorage device 20 andis eluted or released before active pharmaceutical agent 26 is eluted orreleased. That is, active pharmaceutical agent 26 is eluted or releasedafter all of hemostatic agent 24 is eluted or released. In someembodiments, substrate 22 is made from hemostatic agent 24 and activepharmaceutical ingredient 26 is applied to substrate 22, as shown inFIG. 5. In some embodiments, hemostatic agent 24 is positioned betweenactive pharmaceutical ingredient 26 and substrate 22. As such, activepharmaceutical ingredient 26 forms a top layer of anchorage device 20and is eluted or released before active hemostatic agent 24 is eluted orreleased. That is, hemostatic agent 24 is eluted or released after allof active pharmaceutical ingredient 26 is eluted or released.

In embodiments discussed herein wherein anchorage device 20 is a planarsheet, active pharmaceutical ingredient 26 can be applied to at leastone of the top and bottom surfaces of the sheet. That is, activepharmaceutical ingredient 26 may be applied to both the top and bottomsurfaces, or only one of the top and bottom surfaces. In someembodiments, a first active pharmaceutical ingredient 26 is applied tothe top surface and a second active pharmaceutical ingredient 26 isapplied to the bottom surface, wherein the first active pharmaceuticalingredient 26 is different than the second active pharmaceuticalingredient 26. In some embodiments, a first active pharmaceuticalingredient 26 is applied to the top surface and a second activepharmaceutical ingredient 26 is applied to the bottom surface, whereinthe first active pharmaceutical ingredient 26 includes a differentamount of active pharmaceutical ingredient 26 than the second activepharmaceutical ingredient 26.

In embodiments discussed herein wherein anchorage device 20 is a planarsheet, active pharmaceutical ingredient 26 can be applied to the topsurface and hemostatic agent 24 can be applied to the bottom surface. Insome embodiments, one of the top and bottom surfaces includes activepharmaceutical ingredient 26 and hemostatic agent 24 and the other ofthe top and bottom surfaces includes only hemostatic agent 24. In someembodiments, one of the top and bottom surfaces includes activepharmaceutical ingredient 26 and hemostatic agent 24 and the other ofthe top and bottom surfaces includes only active pharmaceuticalingredient 26. In some embodiments, one of the top and bottom surfacesincludes active pharmaceutical ingredient 26 and hemostatic agent 24 andthe other of the top and bottom surfaces does not include hemostaticagent 24 or active pharmaceutical ingredient 26.

In embodiments discussed herein wherein anchorage device 20 is a planarsheet, a first polymer can be applied to one of the top and bottomsurfaces and a second polymer can be applied to the other one of the topand bottom surfaces. In some embodiments, the first polymer includeshemostatic agent 24 and the second polymer includes activepharmaceutical ingredient 26. In some embodiments, one of the first andsecond polymers includes hemostatic agent 24 and active pharmaceuticalingredient 26 and the other of the first and second polymers includesonly hemostatic agent 24. In some embodiments, one of the first andsecond polymers includes hemostatic agent 24 and active pharmaceuticalingredient 26 and the other of the first and second polymers includesonly active pharmaceutical ingredient 26. In some embodiments, one ofthe first and second polymers includes hemostatic agent 24 and activepharmaceutical ingredient 26 and the other of the first and secondpolymers does not include hemostatic agent 24 or active pharmaceuticalingredient 26. In some embodiments, at least one of the first and secondpolymers includes a plurality of discrete layers, such as, for example,a first layer, a second layer, a third layer, a fourth layer, a fifthlayer, etc. In some embodiments, at least one of the layers includes apolymer that is different than a polymer that forms at least one of theother layers.

In some embodiments, the layers each include the same polymer. In someembodiments, the contents of the layers alternate. For example, in someembodiments, the first layer includes hemostatic agent 24, the secondlayer includes active pharmaceutical agent 26, the third layer includeshemostatic agent 24, the fourth layer includes active pharmaceuticalagent 26 and the fifth layer includes hemostatic agent 24, wherein thelayers that include hemostatic agent 24 do not include activepharmaceutical ingredient 26 and the layers that include activepharmaceutical ingredient 26 do not include hemostatic agent 24. In someembodiments, the layers each include hemostatic agent 24, wherein theamount of hemostatic agent 24 in each layer is the same or different. Insome embodiments, the layers each include active pharmaceutical agent26, wherein the amount of active pharmaceutical agent 26 in each layeris the same or different. In some embodiments, the layers each includehemostatic agent 24 and active pharmaceutical agent 26, wherein theamount of hemostatic agent 24 and/or active pharmaceutical agent 26 ineach layer is the same or different.

In embodiments discussed herein wherein anchorage device 20 is a pocketor envelope, active pharmaceutical ingredient 26 can be applied to atleast one of first piece 22 a and second piece 22 b. In someembodiments, only one of first and second pieces 22 a, 22 b includesactive pharmaceutical ingredient 26. In some embodiments, activepharmaceutical ingredient 26 is applied only to the outer surfaces offirst and second pieces 22 a, 22 b. That is, the inner surfaces of firstand second pieces 22 a, 22 b that define cavity C do not have activepharmaceutical ingredient 26 applied thereto. In some embodiments,active pharmaceutical ingredient 26 is applied only to the innersurfaces of first and second pieces 22 a, 22 b. That is, the outersurfaces of first and second pieces 22 a, 22 b do not have activepharmaceutical ingredient 26 applied thereto. In some embodiments,active pharmaceutical ingredient 26 is applied only to the inner surfaceof one of first and second pieces 22 a, 22 b and to the outer surface ofthe other one of first and second pieces 22 a, 22 b.

In embodiments discussed herein wherein anchorage device 20 is a pocketor envelope, a first active pharmaceutical ingredient 26 can be appliedto first piece 22 a and a second active pharmaceutical ingredient 26 canbe applied to second piece 22 b, wherein the second activepharmaceutical ingredient 26 is different than the first activepharmaceutical ingredient 26. In some embodiments, a first activepharmaceutical ingredient 26 is applied to the outer surfaces of firstand second pieces 22 a, 22 b and a second active pharmaceuticalingredient 26 is applied to the inner surfaces of first and secondpieces 22 a, 22 b, wherein the second active pharmaceutical ingredient26 is different than the first active pharmaceutical ingredient 26.

In embodiments discussed herein wherein anchorage device 20 is a pocketor envelope, a first polymer can be applied to one of first and secondpieces 22 a, 22 b and a second polymer can be applied to the other oneof first and second pieces 22 a, 22 b. In some embodiments, the firstand second polymers are the same polymer. In some embodiments, the firstand second polymers are different polymers. In some embodiments, thefirst and second polymers each include hemostatic agent 24 and activepharmaceutical ingredient 26, wherein one of the first and secondpolymers includes more of hemostatic agent 24 than the other of thefirst and second polymers and the polymer that includes more ofhemostatic agent 24 includes less of active pharmaceutical agent 26 thanthe other polymer. In some embodiments, the first polymer includeshemostatic agent 24 and the second polymer includes activepharmaceutical ingredient 26. In some embodiments, one of the first andsecond polymers includes hemostatic agent 24 and active pharmaceuticalingredient 26 and the other of the first and second polymers includesonly hemostatic agent 24. In some embodiments, one of the first andsecond polymers includes hemostatic agent 24 and active pharmaceuticalingredient 26 and the other of the first and second polymers includesonly active pharmaceutical ingredient 26. In some embodiments, one ofthe first and second polymers includes hemostatic agent 24 and activepharmaceutical ingredient 26 and the other of the first and secondpolymers does not include hemostatic agent 24 or active pharmaceuticalingredient 26. In some embodiments, at least one of the first and secondpolymers includes a plurality of discrete layers, such as, for example,a first layer, a second layer, a third layer, a fourth layer, a fifthlayer, etc. In some embodiments, the layers each include differentpolymers.

In embodiments discussed herein wherein anchorage device 20 is a pocketor envelope, a first polymer can be applied to first piece 22 a and asecond polymer can be applied to second piece 22 b. In some embodiments,the first and second polymers are different polymers. In someembodiments, the first and second polymers release hemostatic agent 24and/or active pharmaceutical agent 26 at different rates and/or overdifferent lengths of time. In some embodiments, the first and secondpolymers are different polymers, and the first polymer includes a firstamount of hemostatic agent 24 and/or active pharmaceutical agent 26 andthe second polymer includes a second amount of hemostatic agent 24and/or active pharmaceutical agent 26, the first amount being differentthan the second amount. In some embodiments, the first and secondpolymers are the same polymer, wherein the first polymer includes afirst amount of hemostatic agent 24 and/or active pharmaceutical agent26 and the second polymer includes a second amount of hemostatic agent24 and/or active pharmaceutical agent 26, the first amount beingdifferent than the second amount. In some embodiments, a first polymeris applied to the outer surfaces of first and second pieces 22 a, 22 band a second polymer is applied to the inner surfaces of first andsecond pieces 22 a, 22 b, wherein the first polymer includes a firstamount of hemostatic agent 24 and/or active pharmaceutical agent 26 andthe second polymer includes a second amount of hemostatic agent 24and/or active pharmaceutical agent 26, the first amount being differentthan the second amount. In some embodiments, the first amount is morethan the second amount. In some embodiments, the first amount is lessthan the second amount.

In some embodiments, hemostatic agent 24 and/or active pharmaceuticalingredient 26 is/are configured to elute/release from anchorage device20 into an area surrounding or adjacent to anchorage 20 to reduce orstop bleeding and/or reduce the amount of associated post-surgicalcomplications that can occur with such implantable medical devices, suchas, for example, post-implant infection, pain, excessive scar tissueformation and shrinkage of the prosthesis or mesh, excessive scar tissueformation, limited patient mobility, and/or chronic pain.

In some embodiments, hemostatic agent 24 and/or active pharmaceuticalingredient 26 is configured to elute/release from anchorage device 20into an area surrounding or adjacent to anchorage 20 to reduce or stopbleeding and/or reduce or prevent surgery-related complicationsassociated with the implantable medical device (such as to the “pocket”surrounding the device). For example, an anesthetic agent can be elutedinto the surrounding bodily tissue, bodily fluid, or systemic fluid, toattenuate pain experienced at the implantation site. In another example,replacing the anesthetic agent with an anti-inflammatory agent canreduce the swelling and inflammation associated implantation of the meshsubstrate and/or the implantable medical device. In yet another example,an antimicrobial agent can be provided at a rate of drug releasesufficient to prevent or reduce colonization of substrate 22, theimplantable medical device and/or the surgical implantation site bybacteria, for example, for at least the period following surgerynecessary for initial healing of the surgical incision.

In some embodiments, hemostatic agent 24 and/or active pharmaceuticalingredient 26 may be eluted for up to 30 days. In some embodiments,between about 40% and about 100% of hemostatic agent 24 and/or activepharmaceutical ingredient 26 is/are released over a period of at leastabout 30 hours. In some embodiments, 60% and about 100% of hemostaticagent 24 and/or active pharmaceutical ingredient 26 is/are released overa period of at least about 30 hours. In some embodiments, between about65% and about 100% of hemostatic agent 24 and/or active pharmaceuticalingredient 26 is/are released over a period of at least about 36 hours.In some embodiments, 80% and about 100% of hemostatic agent 24 and/oractive pharmaceutical ingredient 26 is/are released over a period of atleast about 36 hours. In some embodiments, between about 60% and about100% of hemostatic agent 24 and/or active pharmaceutical ingredient 26is/are released over a period of at least about 48 hours. In someembodiments, 80% and about 100% of hemostatic agent 24 and/or activepharmaceutical ingredient 26 is/are released over a period of at leastabout 48 hours. In some embodiments, between about 60% and about 100% ofhemostatic agent 24 and/or active pharmaceutical ingredient 26 is/arereleased over a period of at least about 60 hours. In some embodiments,80% and about 100% of hemostatic agent 24 and/or active pharmaceuticalingredient 26 is/are released over a period of at least about 60 hours.

In some embodiments, anchorage device 20 includes a hydrophiliccomponent, such as, for example, PEG and a crosslinking agent that isapplied to substrate 22. The hydrophilic component and the crosslinkingagent form a hydrogel that absorbs blood and reduces bleeding when incontact with blood or tissue fluid. In some embodiments, the hydrophiliccomponent and the crosslinking agent are sprayed directly onto substrate22. In some embodiments, the hydrophilic component and the crosslinkingagent are provided in a polymer, such as, for example, one or more ofthe polymers discussed herein, and the polymer is applied directly ontosubstrate 22. In some embodiments, the hydrophilic component and thecrosslinking agent are provided in a patch, such as, for example, theVeriset™ hemostatic patch available from Medtronic, Inc., and the patchis applied directly onto substrate 22. In some embodiments, the patchcomprises a plurality of layers. For example, a first layer of the patchcan include a hemostatic agent, such as, for example, oxidizedregenerated cellulose and/or one or more of the hemostatic agentsdiscussed herein. A second layer of the patch can include a crosslinkingagent, such as, for example, trilysine and/or one or more of thecrosslinking agents discussed herein. A third layer of the patch caninclude a hydrophilic agent, such as, for example, PEG and/or one ormore of the hydrophilic agents discussed herein. The second layer of thepatch is positioned between the first and third layers of the patch.

In some embodiments, the hydrophilic component comprises thermogellinghydrogels, PEG -PLGA copolymers, PEG -Poly(N-isopropyl acrylamide),Pluronic (PEO-PPO-PEO triblock), PEG-PCL polymers, PEG-based amphiphiliccopolymers modified by anionic weak polyelectrolytes, (such aspolyacrylic acid, polyglutamic acid) and polymers containing sulfonamidegroups), PEG-based amphiphilic copolymers modified by cationic weakpolyelectrolytes (such as poly (2-vinyl pyridine), Poly(beta-aminoesters), poly (2-(dimethylamino)ethyl methacrylate), multiarm PEGderivatives such as those available from JenKem technology, multiarmedblock and graft PLA copolymers with PEG, PEG with stereo complexedpoly(lactide), acrylated polymers (such as Polyvinylalcohol, dextran,Polyvinylpyrollidone, chitosan, alginate, hyaluronic acid), andcombinations thereof. In some embodiments, the crosslinking agentcomprises one or more agents that induce polymerization of vinyl groupsusing various initiators, light or redox reactions, or by reactions suchas Schiff base formation, Michael type additions , peptide ligation,clock chemistry of functional groups present; one or more agents thatinduce crosslinking by enzymatic reaction (transglutaminase mediatedreaction between carboxamide and amine on proteins),stereo-complexation, metal chelation (alginates using calciumCal2),thermogelation, self-assembly (formation of super helices from proteinchains) inclusion complexation (using cyclodextrin); and combinationsthereof.

Methods

In some embodiments, an anchorage device, such as, for example,anchorage device 20 and a medical device, such as, for example, one ofthe implantable medical devices discussed herein are implanted into abody of a patient. The anchorage device releases a hemostatic agent,such as, for example, hemostatic agent 24 to reduce or prevent bleedingwithin the patient. In some embodiments, the anchorage device alsoreleases an active pharmaceutical agent, such as, for example, activepharmaceutical ingredient 26 to prevent, mitigate, or treat a conditionwithin the patient, such as, for example, a bacterial infection. In someembodiments, the anchorage device releases the hemostatic agent beforethe active pharmaceutical ingredient. In some embodiments, the anchoragedevice releases the hemostatic agent after the active pharmaceuticalingredient. In some embodiments, the anchorage device releases thehemostatic agent and the active pharmaceutical ingredientsimultaneously. In some embodiments, the anchorage device releases thehemostatic agent and/or the active pharmaceutical ingredient uponimplantation of the anchorage device. In some embodiments, the anchoragedevice releases the hemostatic agent and the active pharmaceuticalingredient in alternating sequences. In some embodiments, the anchoragedevice is implanted within the patient without the medical device andthe medical device is coupled to or inserted into the anchorage deviceafter the anchorage device is implanted. In some embodiments, themedical device is coupled to or inserted into the anchorage devicebefore the anchorage device is implanted within the patient and theanchorage device and the medical device are implanted within the patienttogether.

In some embodiments, the implantable medical device is removed from thepatient after the treatment is completed. In some embodiments, theanchorage device remains implanted within the patient after theimplantable medical device is removed. In some embodiments, theanchorage device is removed from the patient after the implantablemedical device is removed. To remove the anchorage device, tissue thatis ingrown within the substrate of the anchorage device can be cut orotherwise detached from the substrate. In some embodiments, a portion ofthe anchorage device may not be removable from the tissue and willremain implanted within the patient.

Kits

In some embodiments, kits are provided that include one or a pluralityof anchorage devices, such as, for example, anchorage devices 20. It iscontemplated that each of the anchorage devices included can have adifferent configuration. In some embodiments, the anchorage devices caninclude different hemostatic agents, such as, for example, hemostaticagent 24 and/or different active pharmaceutical ingredients, such as,for example, different active pharmaceutical ingredients 26. In someembodiments, the anchorage devices can include different amounts of ahemostatic agent, such as, for example, hemostatic agent 24 and/ordifferent amounts of an active pharmaceutical ingredient, such as, forexample, different active pharmaceutical ingredients 26. In someembodiments, the anchorage devices can include different sizes. In someembodiments, the anchorage devices can include different shapes. In someembodiments, the anchorage devices can include different anchoragedevices that are designed for use with different medical devices, suchas, for example, the implantable or non-implantable medical devicesdiscussed herein. In some embodiments, the kits include one or aplurality of medical devices, such as, for example, the implantable ornon-implantable medical devices discussed herein. In some embodiments,the kit includes instructions for use.

Example 1

In one example, an anchorage device having a substrate, such as, forexample, one of the substrates discussed above was prepared. 5 g ofChitosan (HMW, Sigma MKBP1333V) was dissolved in a mixture of 460 mLdistilled water and 40 mL 1M HCl. 10 mL of the viscous solution waspoured into a Teflon petri dish and placed in a hood. After 24 h, thecomposition was dry to touch. It was then placed in a 50° C. oven undervacuum for 24 h.

An equivalent procedure was used to prepare substrates from othermaterials. Details are given in Table A below.

TABLE A # Agent Supplier Lot # Weight Solvent Result 1 Chitosan Sigma 5g 460 mL water + Continuous MKBP1333V 40 mL 1M HCl film 2 PEG 20 KFluka, 12.5 g 25 mL No film 1303367 Dichloromethane 3Polyvinylpyrollidone ISP 5 g 15 mL water + Film (PVP) Technologies, 2 mL1M HCl 0550149110 4 Jello Sugar Free 0.350 g 5 mL water Film strawberryflavor 5 PEG 20 K + Jello 1:1 mix of 1 and 5 No Film

Example 2

In another example, a hemostatic coated mesh substrate was prepared. Aknitted multifilament mesh was taped down on a flat Teflon sheet.Prepared hemostat solutions described above were poured onto the meshand spread using a Gardner Knife. The compositions were allowed to dryovernight in the hood and then at 50° C. under vacuum for 24 hours.Chitosan and PVP solutions and a 1:1 mixture of Chitosan and PVP wereused to prepare hemostat coated meshes.

Hemostatic properties of the anchorage devices prepared in Examples 1and 2 were observed. Water absorption was used as the initial screeningtest for hemostatic properties. A commercial hemostat Surgifoam was usedas the control. Not wetted Surgifoam does not soak water easily, butwetted one works as a sponge. A piece of the hemostatic composition wasplaced on a flat Teflon surface. 3 drops of water were placed in thecenter of the composition and the time for water to absorb and thephysical state of the hemostats were observed. Results are shown in FIG.13.

Example 3

In another example, an anchorage device was prepared wherein theanchorage device had an active pharmaceutical ingredient, such as, forexample, at least one antimicrobial agent was applied to a substrate,such as for example, a hemostatic mesh. A sheet of organic regeneratedcellulose (ORC) made from multifilament fibers was stretched over arectangular frame (10 inches×13 inches). This was coated with a 4%Weight by volume solution containing Rifampin, minocycline and tyrosinepolyarylate (15:15:70 by weight) dissolved in THF:Methanol (9:1 VN)using an ultrasonic spraying machine (Ultrasonic Systems, Inc.,Haverhill, Mass.). The coated mesh was dried under vacuum for 24 h at 50C.

Example 4

In another example, an agent, such as, for example, at least one of theactive pharmaceuticals discussed herein was selectively applied to asubstrate of an anchorage device. Different patterns were created on anORC sheet (made from multifilament fibers) by masking predeterminedareas of the mesh with masking tape. The patterned sheet of ORC wasstretched over a rectangular frame (10 inches×13 inches). This wascoated with a 4% Weight by volume solution containing Rifampin,minocycline and tyrosine polyarylate (15:15:70 by weight) dissolved inTHF:Methanol (9:1 VN) using an ultrasonic spraying machine (UltrasonicSystems, Inc., Haverhill, Mass.). The coated mesh was dried under vacuumfor 24 h at 50 C. The masking tape was peeled off to create meshes withthe predetermined pattern.

Example 5

In another example, an anchorage device having a configuration of apocket, pouch or envelope discussed above was prepared. Two sheets ofthe coated synthetic mesh were coated mesh placed one on top of theother and sealed and cut into the shape using an ultrasonic weld. Theanvil used in the ultrasonic welding resulted in the formation of apouch 2.5″×2.75″ in size, sealed on approximately 3 and one-half sides.By changing the size and shape of the anvil, pouches of different sizesand shapes can be made.

Example 6

In another example, an agent, such as, for example, at least one of thehemostatic agents discussed herein was prepared to be applied to asubstrate of an anchorage device, such as, for example, one of thesubstrates discussed herein. A 5% solution of chitosan (Aldrich, lowmolecular weight) was prepared as follows. 5 g of chitosan, 2.5 g ofsuccinic acid were added to 100 mL of distilled water in a 250-mL glassjar containing a magnetic stir bar. The mixture was stirred at 500 rpmuntil a clear viscous solution was obtained.

Example 7

In another example, an agent, such as, for example, at least one of thehemostatic agents discussed herein was applied to a substrate of ananchorage device, such as, for example, one of the pockets, pouches orenvelopes discussed herein. A piece of Tyvek (blown PTFE) film (sizeequal to that of the inner dimensions of the envelope) was placed withinthe envelope. The envelope was placed on a flat sheet of Teflon. About10 mL of the hemostat solution was poured on the envelope and spreadusing a polypropylene rod. After drying for 24 hours under the hood, theenvelope was removed, excess hemostat was trimmed off and the innerTeflon sleeve was removed. This resulted in the hemostatic agent beingapplied to one side of the envelope. That is, the other side of theenvelope did not include the hemostatic agent.

Example 8

In another example, an agent, such as, for example, at least one of thehemostatic agents discussed herein was applied to a substrate of ananchorage device, such as, for example, one of the pockets, pouches orenvelopes discussed herein. The envelope was mounted on a plasticmandrel, which was then dipped into the viscous solution of hemostat.Excess solution was allowed to drain. The mandrel was dried under vacuumat 80 C for 36 hours. After cooling, the envelope was removed from themandrel. This resulted in the hemostatic agent being applied to bothsides of the envelope.

Example 9

In another example, an anchorage device having a configuration of apocket, pouch or envelope discussed above was prepared. The envelopeswere made from one or more sheets comprising a hemostatic agent and amesh material that is coated with an antibiotic, such as, for example atleast one of the antibiotics discussed herein. The devices may becreated from hemostatic sheets and synthetic mesh by fusing them usingheat, ultrasonic energy or solvent, polymeric solutions or glue, asdiscussed below.

Heat:

1. In one example, two sheets of ORC mesh coated with tyrosine polymerplus Rifampin and Minocycline were placed within the jaws of a PACWORLDbar sealer (using the following conditions: 7 Sec, 140 C, 80 psi. Thesheets were fused together, as discussed herein, and shown in FIG. 14.

2. In one example, one sheet of ORC mesh coated with tyrosine polymer,Rifampin and Minocycline and one sheet of biodegradable mesh made fromglycolide, caprolactone and trimethylene carbonate coated with tyrosinepolymer with Rifampin and Minocycline were placed within the jaws of aPACWORLD bar sealer (using the following conditions: 7 Sec, 140 C, 80psi. The sheets were fused together, as discussed herein and shown inFIG. 15.

3. In one example, one sheet of uncoated ORC mesh and one sheet ofbiodegradable mesh made from glycolide, caprolactone and trimethylenecarbonate coated with tyrosine polymer with Rifampin and Minocyclinewere placed within the jaws of a PACWORLD bar sealer (using thefollowing conditions: 7 Sec, 140 C, 80 psi. The sheets were fusedtogether, as discussed herein and shown in FIG. 16.

4. In one example, one sheet of coated ORC mesh coated with tyrosinepolymer plus Rifampin and Minocycline in a pattern and one sheet ofbiodegradable mesh made from glycolide, caprolactone and trimethylenecarbonate coated with tyrosine polymer with Rifampin and Minocycline ina pattern were placed within the jaws of a PACWORLD bar sealer (usingthe following conditions: 7 Sec, 140 C, 80 psi. The sheets were fusedtogether, as discussed herein. The pattern on the ORC mesh sheet isshown in FIG. 17.

Solvent Based

5. In one example, a solution of tyrosine polymer was placed between twosheets of uncoated ORC. The sheets were clamped together. After dryingfor 36 h under ambient conditions, it was further dried at 80 C for 24hours. The sheets were fused together, as discussed herein.

6. In one example, two sheets of polymer coated ORC were wetted withDMSO. The sheets were clamped together. After drying for 36 h underambient conditions, it was further dried at 80 C for 24 hours. Thesheets were fused together, as discussed herein.

7. In one example, two sheets of polymer coated ORC was wetted with DMF.The sheets were clamped together. After drying for 36 h under ambientconditions, it was further dried at 80 C for 24 hours. The sheets werefused together, as discussed herein.

Adhesive

8. In one example, a small amount of cyanoacrylate glue was placedbetween two sheets of uncoated ORC. The sheets were clamped together anddried at room temperature for 1 hour. The sheets were fused together, asdiscussed herein.

Sewing

9. In one example, two sheets of ORC mesh coated with tyrosine polymerplus Rifampin and Minocycline were sewn together

10. In one example, one sheet of ORC mesh coated with tyrosine polymer,Rifampin and Minocycline and one sheet of biodegradable mesh made fromglycolide, caprolactone and trimethylene carbonate coated with tyrosinepolymer with Rifampin and Minocycline were sewn together

11. In one example, one sheet of uncoated ORC mesh and one sheet ofbiodegradable mesh made from glycolide, caprolactone and trimethylenecarbonate coated with tyrosine polymer with Rifampin and Minocyclinewere sewn together

12. In one example, one sheet of coated ORC mesh coated with tyrosinepolymer plus Rifampin and Minocycline in a pattern and one sheet ofbiodegradable mesh made from glycolide, caprolactone and trimethylenecarbonate coated with tyrosine polymer with Rifampin and Minocycline ina pattern were sewn together.

13. In one example, one sheet of uncoated ORC mesh and one sheet ofbiodegradable film made from tyrosine polymer with Rifampin andMinocycline were sewn together.

14. In one example, one sheet of ORC mesh coated with tyrosine polymerplus Rifampin and Minocycline and one sheet of biodegradable film madefrom tyrosine polymer with Rifampin and Minocycline were sewn togetherwere sewn together.

Example 10

In another example, an agent, such as, for example, at least one of thehemostatic agents discussed herein was selectively applied to asubstrate of an anchorage device. A sheet of biodegradable mesh madefrom glycolide, caprolactone and trimethylene carbonate coated withtyrosine polymer with Rifampin and Minocycline was fixed to a flatsurface. Drops of a solution of Chitosan (5% w/v) in water containingsuccinic acid was applied to the mesh using a syringe. The mesh wasdried overnight at room temperature and then at 80° C. under vacuum for24 h.

Example 11

In another example, agents, such as, for example, at least one of thehemostatic agents discussed herein and at least one of the activepharmaceutical ingredients discussed herein were selectively applied toa substrate of an anchorage device. A 4% Weight by volume solutioncontaining Rifampin, minocycline and tyrosine polyarylate (15:15:70 byweight) dissolved in THF:Methanol (9:1 VN) was first prepared. Fineparticles of a suitable hemostatic agent was suspended in this mixtureand the suspension was sprayed onto a suitable mesh substrate. Afterdrying under ambient condition until the coating was dry to the touch,the mesh was dried in a vacuum oven at 80° C. for 24 to 72 hours. Thehemostatic agents can be selected from any of the hemostatic agentsdiscussed herein and/or tranexamic acid, amino caproic acid (e.g.,epsilon amino caproic acid), aprotinin, natural serine proteaseinhibitors, or polymers such as ORC or chitosan or otherpolysaccharides. In some embodiments, the hemostatic agents can includeArista AH hemostat and a desiccant. In some embodiments, the Arista AHhemostat is a hydrophilic, flowable, sterile, fine, dry white powdermade by crosslinking purified plant starch through a proprietary processinto Microporous Polysaccharide Hemospheres (MPH). In some embodiments,the hemostatic agents can include those discussed by Barnard J, MillnerR, “A Review of Topical Hemostatic Agents for Use in Cardiac Surgery,”Ann Thorac Surg. 2009, 88: 1377-1383. October 1016, which isincorporated herein by reference, in its entirety. In some embodiments,the hemostatic agents can include those discussed by Jill Henley, JerryD. Brewer, “Newer Hemostatic Agents Used in the Practice of DermatologicSurgery,” Dermatology Research and Practice 2013, 1-15, which isincorporated herein by reference, in its entirety. In some embodiments,the hemostatic agents can include those discussed by F. I. Broekema, W.Van Oeveren, J. Zuidema, S. H. Visscher, and R. R. M. Bos, “In vitroanalysis of polyurethane foam as a topical hemostatic agent,” Journal ofMaterials Science, vol. 22, no. 4, pp. 1081-1086, 2011, which isincorporated herein by reference, in its entirety.

Example 12

In another example, anchorage devices having a substrate, such as, forexample, one of the substrates discussed above were prepared wherein thesubstrate was made from fibers that include a hemostatic agent, such as,for example, at least one of the hemostatic agents discussed herein, andfibers that do not include a hemostatic agent. In one example, thefibers that include the hemostatic agent are made from an aqueoussolution that include the hemostatic agent(s). In some embodiments, anactive pharmaceutical ingredient is added to the aqueous solution. Inone example, the fibers that do not include the hemostatic agent arecoextruded with an active pharmaceutical ingredient, such as, forexample, at least one of the active pharmaceutical ingredients discussedherein. The fibers are swelled in some solvent containing the API, suchas, for example, polyurethane or silicone in THF. The fibers thatinclude the hemostatic agent and the fibers that do not include thehemostatic agent are dried, and the dried fibers are used to form amesh. In some embodiments, the fibers that include the hemostatic agentare made as discussed by Pillai, C. K. S.; Paul, W.; Sharma, C. P.Chitin and chitosan polymers: Chemistry, solubility and fiber formation.Prog. Polym. Sci. 2009, 34, 641-678, which is incorporated herein byreference, in its entirety.

Example 13

In another example, an agent, such as, for example, at least one of theactive pharmaceuticals discussed herein was applied to a substrate of ananchorage device such that the agent eluted or released from thesubstrate at a selected rate. The substrate was made from variouscombinations of Glycoprene®, ORC, polymer-coated Glycoprene® (e.g., oneof the tyrosine-derived polymers discussed herein), and polymer-coatedORC (e.g., one of the tyrosine-derived polymers discussed herein). Thesamples were weighed in 20 mL scintillation vials and then immersed in20 mL of phosphate buffered saline (pH 7.4). The vials were allowed toshake at 120 rpm in an incubator at 37° C. At various subsequent timepoints, 1 mL of the buffer was removed for analysis by UPLC. At eachtime point after 1 mL was removed, the buffer was decanted. The vialswere replenished with fresh buffer and returned to the incubator. Thevolume of fresh buffer was gradually reduced from the initial 20 mL to10 mL, 5 mL, and 2 mL in order to maintain a concentration that can bedetected by UPLC.

Samples of coated ORC and coated Glycoprene® were weighed in 20 mLscintillation vials. Samples were initially dissolved in DMSO andallowed to shake for at least 15 minutes. Then, MeOH was added and vialswere allowed to shake for another minimum of 15 minutes. One (1) mL ofeach solution was then filtered through a 0.45 micron PTFE filter andloaded onto the UPLC for analysis. Results below are reported as acumulative % released against time.

Substrates, such as, for example, the substrates discussed herein, wereprepared, as discussed herein, to include coatings (e.g., polymers) thatelute an active pharmaceutical ingredient, such as, for example, atleast one of the active pharmaceutical ingredients discussed herein, atdifferent rates. Ten samples were produced (Samples 1-6 and 9-12), asshown in FIG. 18. In the data provided below, “Tyrx” or “TYRX” refers toa degradable polymer, and in particular, to one or more of thetyrosine-derived polymers discussed herein, wherein the polymer includesat least one active pharmaceutical ingredient.

The active pharmaceutical ingredient(s) or drug(s) in each of Samples1-6 and 9-12 is shown in FIG. 19.

Further details regarding the substrates used in Samples 1-6 and 9-12are provided below.

Weight (mg) TYRX- AIGIS- coated Sample Glycoprene R ORC ORC Sample Drug1 16.1 — — 60.4 1 Elution 2 13.7 — — 57.7 2 3 — 14.4 56.8 — 3 4 — 14.956.1 — 4 5 — 14.7 — 63.6 5 6 — 13.3 — 59.1 6 9 — — — 49.3 9 10 — — —53.2 10 11 — 10.3 — — 11 12 — 11.5 — — 12 Drug 13 — — — 113.9 Content 14— — — 118.1 15 — 87.8 — — 16 — 95.6 — —

AIGIS-R refers to a resorbable mesh substrate that is coated with apolymer, such as, for example, one of the tyrosine-derived polymersdiscussed herein, wherein the polymer includes at least one activepharmaceutical ingredient, as shown below. In the samples that includeGlycoprene®, the Glycoprene® is a mesh that forms the substrate.

The elution rates of the active pharmaceutical ingredients in Samples1-6 and 9-12 are shown in the elution profiles in FIGS. 20A-20T.

In this example, different substrates were examined to test and comparethe elution profiles of the different substrates to determine theeffect, if any, of combining polymer-coated substrates with uncoatedsubstrates.

When uncoated Glycoprene® was added to coated ORC in samples 1 and 2,both minocycline and rifampin releases were below 20% after 2 hours. By24 hours, minocycline release was above 60%, and rifampin release wasover 20%. Minocycline and rifampin releases continued to increasebetween 24 and 30 hours.

With the addition of uncoated ORC to coated Glycoprene® in samples 3 and4, more than 20% minocycline and 20% rifampin was released after 2hours. After 6 hours, minocycline release was over 80% while rifampinrelease was over 60%.

Samples 5 and 6 consisted of both coated Glycoprene® and coated ORC.After 2 hours, minocycline release was over 20% while rifampin releasewas around 50%. By 6 hours, more than 60% of minocycline was released,and more than 20% of rifampin was released. After 24 hours, rifampinrelease was approximately 40% while minocycline release was over 70%.Minocycline and rifampin releases continued to increase between 24 and30 hours.

Minocycline and rifampin elution from samples 9 and 10 (coated ORC) wasbelow 20% after 2 hours. After 24 hours, minocycline release was over60%, while rifampin release was over 20%. Minocycline and rifampinreleases continued to increase between 24 and 30 hours.

For samples 11 and 12 of coated Glycoprene®, more than 80% minocyclineand more than 60% rifampin was released in 2 hours. Minocycline andrifampin release rate gradually increased until it leveled off after 6hours.

In samples 1-6 and 9-10 after 2 hours immersion in PBS, the ORCcomponent can be visually observed to be swollen.

Example 14

To determine the stability of active pharmaceutical ingredients, suchas, for example, one or more of active pharmaceutical ingredients 26when combined with a hemostatic agent, such as, for example, one or moreof hemostatic agents 24, mixtures of rifampin and minocycline wereprepared in phosphate-buffered saline (PBS) with and without tranexamicacid (TXA). The mixtures were tested both at room temperature (RT)(about 23° C.) and at 37° C. As shown in FIG. 21, mixtures of rifampinand minocycline in PBS with and without tranexamic acid havesubstantially the same percentage area of rifampin and minocycline, thusindicating that tranexamic acid does not negatively affect the stabilityof rifampin and minocycline. In particular, the percentage area ofrifampin was substantially the same for mixtures of rifampin andminocycline in PBS with and without tranexamic acid, regardless of thetemperature; the percentage area minocycline was substantially the samefor mixtures of rifampin and minocycline in PBS with and withouttranexamic acid when the mixtures were at the same temperature

Example 15

To determine the elution of active pharmaceutical ingredients, such as,for example, one or more of active pharmaceutical ingredients 26 from apolymer, such as, for example, one of the polymers discussed herein, invitro when the active pharmaceutical ingredients are combined with ahemostatic agent, such as, for example, one or more of hemostatic agents24, in vitro elution of rifampin and minocycline from polymers in thep22-27.5 family containing different amounts of tranexamic acid wasevaluated in a PBS buffer over 25 hours. B1=PBS pH 7.4; B2=PBS, pH7.4+TXA (0.05 mg/mL); B3=PBS, pH 7.4+TXA (5 mg/mL). The elution ratesfor rifampin and minocycline are shown in FIG. 22. As shown in FIG. 22,the elution rates of rifampin and minocycline were not affected by thepresence of TXA in the release media.

Example 16

To determine the sustained release of active pharmaceutical ingredients,such as, for example, one or more of active pharmaceutical ingredients26 from a polymer, such as, for example, one of the polymers discussedherein, when the active pharmaceutical ingredients are combined with ahemostatic agent, such as, for example, one or more of hemostatic agents24, thin and thick solvent cast films containing rifampin (Rif) andtranexamic acid were prepared. Thin and thick solvent cast filmscontaining minocycline (Min) and tranexamic acid were also prepared. Thetranexamic acid phase was separated in each of the films. Thin films hada thickness of about 30 microns and thick films had a thickness of about400 microns. Elution of rifampin and minocycline was measured over about30 hours. The percentage of rifampin and minocycline released at 2hours, 6 hours and 24 hours was recorded. As shown in FIG. 23, the thinfilms released rifampin and minocycline more quickly than the thickfilms at the same time intervals. However, for each set of films (thickand thin), rifampin and minocycline were shown to elute at similarrates.

Example 17

Tests were conducted to compare the time required to induce bloodclotting in vitro when different amounts of hemostatic agent isadministered in the presence of TYRX (degradable mesh coated withP22-27.5 containing rifampin and minocycline), as shown in FIG. 24.Clotting time was increased when higher amounts of TXA was present (1.6mg TXA vs 200 mg of TXA), as shown in FIG. 28.

Example 18

Tests were conducted to compare the time required for differenthemostatic agents to induce blood clotting in vitro versus the timerequired to induce blood clotting in vitro when no hemostatic agent isadministered. In particular, the time required to induce blood clottingwas plotted for blood alone, TYRX, Surgicel, TYRX with 1.6 mg of TXA,1.2 mg of TXA alone, and TYRX with 200 mg of TXA. In this example, TYRXrefers to a Glycoprene mesh that is coated with P22-27.5 (a polymer inthe P22-X family) containing Rifampin and Minocycline. As shown in FIG.25, blood alone and TYRX were both effective to induce blood clotting inabout 14 minutes; Surgicel was effective to induce blood clotting inabout 17 minutes; TYRX with 1.6 mg of TXA was effective to induce bloodclotting in about 12 minutes; 1.2 mg of TXA alone was effective toinduce blood clotting in about 19 minutes; and the p22-27.5 polymerhaving 200 mg of TXA was effective to induce blood clotting in about 32minutes, thus indicating that TYRX with low amount of TXA (1.6 mg) mayinduce blood clotting better than TYRX with 200 mg TXA.

Example 19

To determine the impact, if any, of a hemostatic agent, such as, forexample, one or more of hemostatic agents 24 on bacterial attachment,three samples were prepared. The first sample included TYRX, a polymerin the p22-xx family (P22-27.5-TYRX); the second sample included TYRXand tranexamic acid (TYRX+TXA); and the third sample included anextracellular matrix (ECM) to be used as a control. In this example,TYRX refers to a glycoprene mesh that is coated with P22-27.5 (a polymerin the P22-X family) containing rifampin and minocycline. The sampleswere each suspended in 3 mL of a Brain Heart Infusion (BHI) medium at37° C. for 24 hours. The samples were each inoculated with 2× ColonyForming Units (CFU)/mL of a clinical strain of Methicillin-resistantStaphylococcus aureus (MRSA). After 24 hours, each of the samples wasrinsed twice and bacterial attachment was visualized by Live/Deadstaining and imaged with Leica DM RXE microscope attached to a TCS SP2AOBS confocal system (Leica Microsystems, Exton, Pa.). As shown in FIG.26, the TYRX and TYRX+TXA samples exhibited less bacterial attachmentthan the ECM control.

Example 20—Chitosan Solutions for Preparing Films

1 gram of Chitosan (Sigma) was added to 100 mL of Aqueous Acetic acid(1% Acetic acid). The mixture was stirred using a magnetic stir baruntil no solids remained.

Films were cast by pouring on 10 mL of the chitosan solution onto aTEFLON sheet. The solution was covered with a Petri dish dried in aventilated hood 24 hrs. The Petri dish was removed and the films driedfor an addition 72 hrs. A transparent film was obtained.

50 mg of Tranexamic acid was added to 10 g of the chitosan solutionprepared as described above in a 20-mL scintillation vial. The vial wascapped and placed on a shaker. The contents were shaken for 1 hr, whenall the TXA had dissolved.

Films were cast by pouring on to a TEFLON sheet. The solution wascovered with a Petridis dried in a ventilated hood 24 hrs. The Petridiswas removed and the films dried for an addition 72 hrs. A transparentfilm was obtained.

50 mg of Tranexamic acid, 50 mg of Rifampin, 50 mg of Minocycline-HCLwas added to 10 g of the chitosan solution prepared as described abovein a 20-mL scintillation vial. The vial was capped and placed on ashaker. The contents were shaken for 1 hr, when all the drugs had haddissolved.

Films were cast by pouring on to a TEFLON sheet. The solution wascovered with a Petri dish dried in a ventilated hood 24 hrs. The Petridish was removed and the films dried for an addition 72 hrs. Atransparent red film was obtained.

Two kinds of meshes were used in these experiments—a monofilament meshof polypropylene (non-absorbable) and a multifilament absorbable mesh(GLYCOPRENE II), which is made from glycolide, caprolactone andtrimethylene carbonate.

Strips of mesh approximately 1 cm×3 cm were hand dipped into thesolutions of chitosan, Chitosan+Tranexamic acid and Chitosan+Tranexamicacid+Rifampin+Minocycline-HCl. These solutions were prepared asdescribed above. Excess solution was removed using Kim wipes and wetstrips were hung to dry in a hood. The coated meshes were dry to thetouch after overnight drying.

Example 21—Avoiding Crystallization in Films

To assess how to avoid crystallization in films, four samples wereprepared—sample J, sample L, sample B2 and sample F2. Sample J includesa polymer in the p22-xx family (P22-27.5-TYRX), rifampin, minocyclineand tranexamic acid. Sample L includes a polymer in the p22-xx family(P22-27.5-TYRX), rifampin, minocycline, tranexamic acid and water.Sample B2 includes a polymer in the p22-xx family (P22-27.5-TYRX) andtranexamic acid. Sample F2 includes a polymer in the p22-xx family(P22-27.5-TYRX), tranexamic acid and water.

The samples were imaged using a digital microscope under a variety ofillumination conditions and magnifications of 50×, 100×, and 200×.Transmitted crossed-polarized illumination highlighted anisotropic,apparently crystalline features in several films, as shown in FIG. 27.

Transmitted crossed-polarized illumination highlighted anisotropic,apparently crystalline features in films containing TXA. However, theapparently crystalline features were not observed in sample F2 or sampleL, as shown in FIG. 27. Both of these samples were made with 1 mLaqueous TXA.

Example 22—Preparation of Electrospun Mats

Some of the properties of electro spun fibers are their high surfacearea, inherent 3 dimensional features and tunable porosity. In electrospinning, a thin stream of charged polymer solution is ejected from aspinneret in the presence of a high electric field (in the range of 105to 106 V/m) applied between a conducting collector and the spinneret.Due to the application of electrostatic potential, the jet will stretchand whip around along with solvent evaporation because of the columbicrepulsion between the surface charges. The resulting mass of fine fiber(nanofibers) is then collected on the target electrodes.

This technique can be used to molecules within the fiber matrix. If thedrug is soluble in the polymer solution, then the drugs will behomogeneously distributed (dissolved) within the fiber. If however, thedrug particles are not soluble in the polymer matrix, then the insolubleparticles will be entrapped within the fiber matrix.

This technique can therefore be used to encapsulate water soluble activepharmaceutical ingredients and/or hemostatic agents (such as, forexample tranexamic acid, peptides, proteins) which have poor solubilityin organic solvents. Typically, a solution of the organic soluble activepharmaceutical ingredients and/or hemostatic agents with a particle sizeof less than 100 microns are suspended in an organic solution of apolymer and subjected to the electrospinning process, resulting inmatrix of polymer fibers containing particles of drug. This technique isuseful since high payloads of drugs can be incorporated into thesubstrate. The polymer solution may optionally contain other organicsoluble compounds, including active pharmaceutical ingredients and/orhemostatic agents. More than one organic insoluble compound can besuspended in the polymer solution.

For example, the organic solution may be mixture of P22-27.5+ Rifampin(10% w/w relative to polymer) and Minocycline (10% w/w relative topolymer) dissolved in a 9:1 mixture of THF:Methanol. 10% of fine powderof TXA (10% W/W relative to polymer) may be suspended in this solutionand subjected to electrospray. The resulting nanofiber mat wouldtherefore contain 10% each of Rifampin and Minocycline dissolved in thefibers and 10% TXA entrapped between fibers.

It will be understood that various modifications may be made to theembodiments disclosed herein. Therefore, the above description shouldnot be construed as limiting, but merely as exemplification of thevarious embodiments. Those skilled in the art will envision othermodifications within the scope and spirit of the claims appended hereto.

1-20. (canceled)
 21. A surgical system comprising: an anchorage deviceconfigured to secure an implantable medical device within a patient'sanatomy, the anchorage device comprising a substrate comprising a firstpiece and a second piece that is joined with the first piece to form apocket configured for disposal of the implantable medical device, thefirst piece being made entirely of a hemostatic agent.
 22. The surgicalsystem recited in claim 21, wherein the hemostatic agent is tranexamicacid.
 23. The surgical system recited in claim 21, wherein thehemostatic agent is collagen.
 24. The surgical system recited in claim21, wherein the hemostatic agent is a first hemostatic agent, thesubstrate comprising a coating that covers at least a portion of thesubstrate, the coating comprising a second hemostatic agent.
 25. Thesurgical system recited in claim 24, wherein the first hemostatic agentis collagen and the second hemostatic agent is tranexamic acid.
 26. Thesurgical system recited in claim 21, further comprising the implantablemedical device, the implantable medical device being selected from thegroup consisting of cardiac monitors, defibrillators, pacemakers andleft ventricle assist devices.
 27. The surgical system recited in claim21, wherein the hemostatic agent is a first hemostatic agent, the firstpiece and the second piece each comprising a coating that covers atleast a portion of the first piece and at least a portion of the secondpiece, the coating comprising a second hemostatic agent.
 28. Thesurgical system recited in claim 27, wherein the first hemostatic agentis collagen and the second hemostatic agent is tranexamic acid.
 29. Thesurgical system recited in claim 21, wherein the hemostatic agent is afirst hemostatic agent, the first piece comprising a first coating thatcovers at least a portion of the first piece, the second piececomprising a second coating that covers at least a portion of the secondpiece, the first coating being different from the second coating, atleast one the first coating and the second coating comprising a secondhemostatic agent.
 30. The surgical system recited in claim 29, whereinthe first hemostatic agent is collagen and the second hemostatic agentis tranexamic acid.
 31. The surgical system recited in claim 21, whereinthe hemostatic agent is a first hemostatic agent, the anchorage devicecomprising a polymer that covers of at least one of the first piece andthe second piece, the polymer having a second hemostatic agent dispersedtherein.
 32. The surgical system recited in claim 31, wherein the firsthemostatic agent is collagen and the second hemostatic agent istranexamic acid.
 33. The surgical system recited in claim 31, whereinthe polymer is poly(D,L-lactide-co-glycolide).
 34. The surgical systemrecited in claim 31, wherein the polymer is a tyrosine-derivedpolyarylate.
 35. The surgical system recited in claim 21, wherein thehemostatic agent is a first hemostatic agent, the first piece comprisinga first polymer that covers at least a portion of the first piece, thesecond piece comprising a second polymer that covers at least a portionof the second piece, the first polymer having a second hemostatic agentdispersed therein, the second polymer having a combination of rifampinand minocycline dispersed therein.
 36. The surgical system recited inclaim 35, wherein: the first hemostatic agent is collagen; the secondhemostatic agent is tranexamic acid; the first polymer ispoly(D,L-lactide-co-glycolide); and the second polymer is atyrosine-derived polyarylate.
 37. The surgical system recited in claim21, wherein the hemostatic agent is a first hemostatic agent, the firstpiece comprising a first polymer that covers at least a portion of thefirst piece, the second piece comprising a second polymer that covers atleast a portion of the second piece, the first polymer having acombination of rifampin and minocycline dispersed therein, the secondpolymer having a second hemostatic agent dispersed therein.
 38. Thesurgical system recited in claim 37, wherein: the first hemostatic agentis collagen; the second hemostatic agent is tranexamic acid; the firstpolymer is a tyrosine-derived polyarylate; and the second polymer ispoly(D,L-lactide-co-glycolide).
 39. A surgical system comprising: animplantable medical device selected from the group consisting of cardiacmonitors, defibrillators, pacemakers and left ventricle assist devices;and an anchorage device configured to secure the implantable medicaldevice within a patient's anatomy, the anchorage device comprising asubstrate comprising a first piece and a second piece that is joinedwith the first piece to form a pocket configured for disposal of theimplantable medical device, the first piece being made entirely ofcollagen, the first piece comprising a first polymer that covers atleast a portion of the first piece, the second piece comprising a secondpolymer that covers at least a portion of the second piece, wherein thefirst polymer is poly(D, L-lactide-co-glycolide) and has tranexamic aciddispersed therein, and wherein the second polymer is a tyrosine-derivedpolyarylate and has a combination of rifampin and minocycline dispersedtherein.
 40. A surgical system comprising: an implantable medical deviceselected from the group consisting of cardiac monitors, defibrillators,pacemakers and left ventricle assist devices; and an anchorage deviceconfigured to secure the implantable medical device within a patient'sanatomy, the anchorage device comprising a substrate comprising a firstpiece and a second piece that is joined with the first piece to form apocket configured for disposal of the implantable medical device, thefirst piece being made entirely of collagen, the first piece comprisinga first polymer that covers at least a portion of the first piece, thesecond piece comprising a second polymer that covers at least a portionof the second piece, wherein the first polymer is a tyrosine-derivedpolyarylate and has a combination of rifampin and minocycline dispersedtherein, and wherein the second polymer ispoly(D,L-lactide-co-glycolide) and has tranexamic acid dispersedtherein.